Kras g12s and g12c inhibitors

Abstract

The present invention relates to compounds that inhibit KRas G12S and / or KRas G12C. In particular, the present invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

Description

KRAS G12S AND G12C INHIBITORS FIELD OF THE INVENTION

[0001] The present invention relates to compounds that inhibit KRas G12S and / or KRas G12C. In particular, the present invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor. BACKGROUND OF THE INVENTION

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch cycling between inactive (GDP- bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol.13:394-401).

[0003] The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 -30% of lung adenocarcinomas. (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038 / nrd428). Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma. KRAS G12S mutations were present in 2% of colorectal carcinoma patients, 0.6% of ovarian cancer patients, 0.5% of non-small cell lung carcinomas patients, 0.2% of bladder and gastric cancers, and in 0.1% of pancreatic ductal adenocarcinoma, breast cancer, and endometrial cancer patients (The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through An International Consortium, Cancer Discovery 2017.Cohort v.13.1-public).

[0004] The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractive target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large-scale discovery efforts to developinhibitors of KRas for treating cancer, very few KRas inhibitors have demonstrated sufficient safety and / or efficacy to obtain regulatory approval.

[0005] Compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi: 10.1002 / anie201201358) as well recent advances in the covalent targeting of an allosteric pocket of KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett.9:1230-1234). Clearly there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants, including KRas G12S and KRas G12C.

[0006] Thus, there is a need to develop new KRas G12S and / or KRas G12C inhibitors that demonstrate sufficient efficacy for treating KRas G12S-mediated cancer and / or KRas G12C- mediated cancer. SUMMARY OF THE INVENTION

[0007] In one aspect of the invention, compounds are provided that inhibit KRas G12S and / or KRas G12C activity.

[0008] In certain embodiments, the compounds are represented by Formula (Ia) or (Ib):Formula (Ia) Formula (Ib)

[0009] or a pharmaceutically acceptable salt thereof, wherein:, ,

[0011] B is selected from:

[0012] X is a bond, N, methylene, ethylene or propylene;

[0013] D is CO or SO2;

[0014] E is N or CR10;

[0015] Y is a bond, O or NR5;

[0016] Z is hydrogen, C1-C4 alkyl, heterocyclyl, heteroaryl or aryl, where Z is optionally substituted with 1-3 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, oxo, OR12, N(R12)2 , COR12and cyano;

[0017] each R2is independently hydrogen, hydroxy, halogen, C1-C3 alkyl, spiro cyclopropyl, C1- C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF2, HC(=O)-, -OC(O)N(R5)2, -CO2R5, -CO2N(R5)2, =CH2, =CHR11or =C(R11)2, wherein R2is optionally substituted with one or more R4;

[0018] R3is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with one or more R8;

[0019] R4is hydrogen, halogen or C1 – C3 alkyl;

[0020] each R5is independently hydrogen or C1 – C3 alkyl;

[0021] each R6is independently hydrogen, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl or heteroaryl, or two R6join to form C3-C6 cycloalkyl or heterocycle;

[0022] each R8is independently halogen, cyano, hydroxy, cycloalkyl, C1 - C3 alkyl, -S-C1 - C3 alkyl, C2 – C4 alkenyl, C2 – C4 alkynyl, C2 – C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1 - C3 haloalkyl, -O- C1 - C3 haloalkyl, or -S- C1 - C3 haloalkyl;

[0023] each R9is independently hydrogen, C1-C4 alkyl, methoxy, CH2-methoxy, hydroxy, CH2F, CF2, CF3, C-CN, cyclopropyl, or two R9on the same or different carbon atoms join to form a C1- C2 alkylene bridge or a spirocycle;

[0024] each R10is hydrogen, halogen, CH2F, CHF2, CF3, C1–C3 alkyl, cyclopropyl, OR12, or N(R12)2;

[0025] each R11is halogen or C1-C3 alkyl,

[0026] R12is C1-C3 alkyl, and

[0027] R13is H or forms a ring with A.

[0028] In another aspect of the invention, pharmaceutical compositions are provided comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0029] In yet another aspect of the invention, methods for inhibiting KRas G12S and / or KRas G12C activity in a in a cell, comprising contacting the cell with a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0030] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0031] Also provided are methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0032] Also provided herein is a method of treating a KRas G12S-associated and / or KRas G12C- associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0033] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[0034] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.

[0035] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof for use in the inhibition of KRas G12S and / or KRas G12C.

[0036] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12S-associated and / or KRas G12C-associated disease or disorder.

[0037] Also provided herein is the use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0038] Also provided herein is a use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12S and / or KRas G12C.

[0039] Also provided herein is the use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12S-associated and / or KRas G12C-associated disease or disorder.

[0040] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12S mutation (i.e., a KRas G12S-associated cancer) or a KRas G12C mutation (i.e., a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0041] Also provided herein is a process for preparing a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof.

[0042] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0043] The present invention relates to inhibitors of KRas G12S and / or KRas G12C. In particular, the present invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions comprising a therapeutically effective amount of the compounds and methods of use therefor. DEFINITIONS

[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.

[0045] As used herein, “KRas G12S” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp.

[0046] As used herein, a “KRas G12S inhibitor” refers to compounds of the present invention that are represented by Formula (Ia) or (Ib), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12S.

[0047] A "KRas G12S-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12S mutation. A non-limiting example of a KRas G12S-associated disease or disorder is a KRas G12S-associated cancer.

[0048] As used herein, “KRas G12C” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Cys.

[0049] As used herein, a “KRas G12C inhibitor” refers to compounds of the present invention that are represented by Formula (Ia) or (Ib), as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C.

[0050] A "KRas G12C-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.

[0051] As used herein, the term “subject,” "individual," or "patient," used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRas G12S or a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a KRas G12S or a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a KRas G12S or a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a KRas G12S or a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12S gene-associated cancer or a KRas G12C gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has atumor that has a KRas G12S or a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0052] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the patient has KRas G12S or KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12S-associated or a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12S-associated or a KRas G12C-associated cancer, and / or a patient that has an increased risk of developing a KRas G12S-associated cancer or a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.

[0053] The term “regulatory agency” is a country’s agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0054] The term "acyl" refers to -C(O)CH3.

[0055] The terms "C1-C6 alkyl", “C1-C4 alkyl” and “C1-C3 alkyl” as employed herein refers to straight and branched chain aliphatic groups having from 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, respectively. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0056] The terms “C1-C3 haloalkyl” and “C1-C4 haloalkyl” refer to a C1-C3 alkyl chain or C1-C4 alkyl chain, respectively, as defined herein in which one or more hydrogen has been replaced by a halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.

[0057] An "C1-C4 alkylene," group is a C1-C4 alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, 2-2-dimethyl ethylene, propylene, and butylene.

[0058] The terms “C1-C3 alkoxy” and “C1 – C4 alkoxy” refer to –OC1 – C3 alkyl and -OC1-C4 alkyl, respectively, wherein the alkyl portion is as defined herein above.

[0059] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted with one or more RXgroups as defined herein. The cycloalkyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term “cycloalkyl” also includes bridged cycloalkyls, such as bicyclo[1.1.1]pentanyl.

[0060] As used herein, the terms “C1-C3 hydroxyalkyl” and “C1-C4 hydroxyalkyl” refer to –C1- C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0061] As used herein, the term “C2-C4 hydroxyalkynyl” refers to -C2-C4 alkynylene-OH.

[0062] An "aryl" group is a C6-C14 aromatic moiety comprising one to three aromatic rings, which is optionally substituted with one or more substituents as defined herein. As one embodiment, the aryl group is a C6-C10aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. “Aryl” also refers to bicyclic or tricyclic ring systems in which one or two rings, respectively, of said aryl ring system may be saturated or partially saturated, and wherein if said ring system includes two saturated rings, said saturated rings may be fused or spirocyclic. An example of an aryl ring system comprising two saturated rings wherein the rings are spirocyclic includes the following ring system:.

[0063] An "araC1-C6 alkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. An example of an aralkyl group is (C6-C10)aryl(C1- C6)alkyl-, including, without limitation, benzyl, phenethyl, and naphthylmethyl. Another example of an aralkyl group is (C6-C10)aryl(C1-C3)alkyl-, again including, without limitation, benzyl, phenethyl, and naphthylmethyl. An example of a substituted araC1-C6 alkyl is wherein the alkyl group is substituted with hydroxyalkyl.

[0064] A "heterocyclyl" or "heterocyclic" group is a ring structure having from 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to N-O, and the ring S atom may be oxidized to SO or SO2, the remainder of the ring atoms being carbon. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system. The heterocyclic group is optionally substituted with one or more R6on ring carbon or ring nitrogen at one or more positions, wherein R6is as defined for Formula I. The heterocyclic group is also independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizine], hexahydro-1H-pyrrolizinyl, tetrahydro-1H-pyrrolizinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(1H)- oxide, tetrahydro-2H-thiopyranyl 1-oxide and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0065] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S. Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4- triazolyl, and xanthenyl. “Heteroaryl” also refers to bicyclic ring systems having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S in which one ring system may be saturated or partially saturated.

[0066] As used herein, “an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of KRas G12S and / or KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0067] As used herein, a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12S and / or KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0068] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0069] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.COMPOUNDS

[0070] In one aspect of the invention, compounds are provided represented by Formula (Ia) or (Ib):or a pharmaceutically acceptable salt thereof, wherein:

[0072] B is selected from:

[0073] X is a bond, N, methylene, ethylene or propylene;

[0074] D is CO or SO2;

[0075] E is N or CR10;

[0076] Y is a bond, O or NR5;

[0077] Z is hydrogen, C1-C4 alkyl, heterocyclyl, heteroaryl or aryl, where Z is optionally substituted with 1-3 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, oxo, OR12, N(R12)2, COR12and cyano;

[0078] each R2is independently hydrogen, hydroxy, halogen, C1-C3 alkyl, spiro cyclopropyl, C1- C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF2, HC(=O)-, -OC(O)N(R5)2, -CO2R5, -CO2N(R5)2, =CH2, =CHR11or =C(R11)2, wherein R2is optionally substituted with one or more R4;

[0079] R3is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with one or more R8;

[0080] R4is hydrogen, halogen or C1 – C3 alkyl;

[0081] each R5is independently hydrogen or C1 – C3 alkyl;

[0082] each R6is independently hydrogen, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl or heteroaryl, or two R6join to form C3-C6 cycloalkyl or heterocycle;

[0083] each R8is independently halogen, cyano, hydroxy, cycloalkyl, C1 - C3 alkyl, -S-C1 - C3 alkyl, C2 – C4 alkenyl, C2 – C4 alkynyl, C2 – C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1 - C3 haloalkyl, -O- C1 - C3 haloalkyl, or -S- C1 - C3 haloalkyl;

[0084] each R9is independently hydrogen, C1-C4 alkyl, methoxy, CH2-methoxy, hydroxy, CH2F, CF2, CF3, C-CN, cyclopropyl, or two R9on the same or different carbon atoms join to form a C1- C2 alkylene bridge or a spirocycle;

[0085] each R10is hydrogen, halogen, CH2F, CHF2, CF3, C1–C3 alkyl, cyclopropyl, OR12, or N(R12)2;

[0086] each R11is halogen or C1-C3 alkyl,

[0087] R12is C1-C3 alkyl, and

[0088] R13is H or forms a ring with A.

[0089] In certain such embodiments, Formula (Ia) is Formula IA:.

[0090] In other such embodiments, Formula (Ia) is Formula IB:.

[0091] In certain embodiments, X is methylene.

[0092] In certain embodiments, X is ethylene.

[0093] In certain embodiments, X is a bond.

[0094] In certain embodiments, X is propylene.

[0095] In one embodiment, Y is NR5.

[0096] In one embodiment, Y is a bond.

[0097] In one embodiment, Y is O.

[0098] In one embodiment, Z is hydrogen.

[0099] In another embodiment, Z is C1-C4 alkyl, optionally substituted with 1-3 halogens.

[0100] In yet another embodiment, Z is aryl, optionally substituted with 1-3 halogens, cyano, or C1-C4 haloalkyl. In an aspect of this embodiment, the aryl is phenyl.

[0101] In yet another embodiment, Z is heteroaryl, optionally substituted with 1-2 C1-C4 alkyl. In an aspect of this embodiment, the heteroaryl is pyrazolyl or pyridinyl.

[0102] In yet another embodiment of the invention, Z is heterocyclyl, optionally substituted with oxo. In an aspect of this embodiment, the heterocyclyl is oxazolidine.

[0103] On one embodiment, two R9join to form a methylene bridge, or two R9join to form an ethylene bridge.

[0104] In certain embodiments, R5is hydrogen.

[0105] In certain embodiments, R5is C1 – C3 alkyl. In certain of these embodiments, the C1 – C3 alkyl is methyl.

[0106] In one embodiment, R2is halogen. In an aspect of this embodiment R2is fluoro.

[0107] In another embodiment, R2is =CHR11.

[0108] In yet another embodiment, R2is =C(R11)2.

[0100] In one embodiment of the compounds of Formula (Ia) or (Ib), Formula (IA) and / or Formula (IB), R3is aryl optionally substituted with one or more R8. In certain embodiments, the aryl is selected from the group consisting of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 2,3- dihydro-1H-indenyl, wherein each is optionally substituted with one or more R8.

[0101] In one embodiment, the aryl is phenyl substituted with one or more R8groups. In one embodiment, the aryl is phenyl substituted with one or more R8groups independently selected from halogen, C1 - C3 alkyl and cycloalkyl. In certain embodiments the phenyl is substituted with two R8groups. In certain embodiments the phenyl is substituted with two R8groups, wherein the one R8group is halogen and the other R8group is C1 - C3 alkyl or cycloalkyl.

[0102] In one embodiment, the aryl is 2,3-dihydro-1H-indenyl optionally substituted with one or more R8. In one embodiment, the aryl is 2,3-dihydro-1H-indenyl optionally substituted with one R8. In one embodiment, R8is C1 – C alkyl.

[0103] In one embodiment, the aryl is naphthyl substituted with one or more R8groups. In one embodiment, the aryl is naphthyl substituted with one or more R8groups independently selected from halogen, cyano, hydroxy, C1 - C3 alkyl, -S-C1 - C3 alkyl, C2 – C4 alkenyl, C2 – C4 alkynyl, C2 – C4 hydroxyalkynyl, C1-C3 cyanoalkyl, cycloalkyl, triazolyl, C1-C3 haloalkyl and -O-C1-C3 haloalkyl.

[0104] In one embodiment, the aryl is naphthyl substituted with hydroxy. In one embodiment, the aryl is naphthyl substituted with halogen. In certain embodiments, the halogen is chlorine, fluorine or bromine. In other embodiments, the halogen is chlorine. In other embodiments, the halogen is fluorine.

[0105] In one embodiment, the aryl is naphthyl substituted with C1 - C3 alkyl, wherein the C1 - C3 alkyl is methyl or ethyl.

[0106] In one embodiment, the aryl is naphthyl substituted with C2 – C4 alkenyl. In certain embodiments, the C2 – C4 alkenyl is prop-2-enyl.

[0107] In one embodiment, the aryl is naphthyl substituted with C2 – C4 alkynyl. In certain embodiments, the C2 – C4 alkynyl is ethyne or prop-2-ynyl.

[0108] In one embodiment, the aryl is naphthyl substituted with cycloalkyl. In certain embodiments, the cycloalkyl is cyclopropyl.

[0109] In one embodiment, the aryl is naphthyl substituted with one or two R8, wherein each R8is halogen, cyano, hydroxy, C1 - C3 alkyl, -S-C1 - C3 alkyl, C2 – C4 alkenyl, C2 – C4 alkynyl, C2 – C4 hydroxyalkynyl, C1 – C3 cyanoalkyl, or triazolyl. In one embodiment, the aryl is naphthyl substituted with two R8groups independently selected from halogen, hydroxy, C1 - C3 alkyl and C2 – C4 alkynyl. In another embodiment, one R8is hydroxy and the other R8is C1 - C3 alkyl, halogen or C2 – C4 alkynyl, or one R8is halogen and the other R8is C1 – C3 or C2 – C4 alkynyl

[0110] In one embodiment, the aryl is naphthyl substituted with three R8groups wherein the first R8group is halogen, the second R8group is hydroxy, and the third R8group is C1 - C3 alkyl or C2 – C4 alkynyl.

[0111] In one embodiment of the compounds of Formula (Ia) or (Ib), Formula (IA) and / or Formula (IB), R3is heteroaryl optionally substituted with one or more R8. In one embodiment, the heteroaryl is isoquinolinyl, indazolyl, or benzo[d][1,3]dioxolyl optionally substituted with one or more R8. In one embodiment, the heteroaryl is indazolyl optionally substituted with one or more R8. In one embodiment, the heteroaryl is indazolyl optionally substituted with C1-C3 alkyl or C1 – C3 alkyl and halogen. In other embodiments, the heteroaryl is isoquinolinyl optionally substituted with one or more R8. In other embodiments, the heteroaryl is isoquinolinyl optionally substituted withhalogen or C2-C4 alkynyl. In certain embodiments, the heteroaryl is benzo[d][1,3]dioxolyl optionally substituted with two R8groups. In certain embodiments, the heteroaryl is benzo[d][1,3]dioxolyl optionally substituted with two R8groups, wherein each R8group is an independently selected halogen. In one embodiment, the two halogens are gem-difluoro substitutions. In another embodiment R3 is indazolyl substituted with two R8, where one R8is halogen and the other R8is C1-C3 alkyl.

[0112] In one embodiment of the compounds of Formula (Ia) or (Ib), Formula (IA) and / or Formula (IB), R4is hydrogen.

[0113] In one embodiment of the compounds of Formula (Ia) or (Ib), Formula (IA) and / or Formula (IB), R4is halogen. In one embodiment, R4is fluorine. In one embodiment, R4is chlorine.

[0114] In one embodiment of the compounds of Formula (Ia) or (Ib), Formula (IA) and / or Formula (IB), R4is C1 – C3 alkyl. In one embodiment, R4is methyl.

[0115] Nonlimiting examples of compounds of Formula (Ia) or (Ib), Formula (IA) and / or Formula (IB) are selected from the group consisting of:, ,,, ,,, ,,, ,,, ,,, ,,

[0116] and pharmaceutically acceptable salts thereof.

[0117] In one embodiment, the compounds of Formula (Ia) or (Ib), Formula (IA) and / or Formula (IB), include bis-hydrochloride, formic acid, bis-formic acid, tris-hydrochloride, trifluoroacetic acid, bis-trifluoroacetic acid, and tris-trifluoracetic acid salts of the above compounds. The compounds of Formula (Ia) or (Ib), or pharmaceutically acceptable salt thereof may be formulated into pharmaceutical compositions. PHARMACEUTICAL COMPOSITIONS

[0118] In another aspect, the invention provides pharmaceutical compositions comprising a KRas G12S and / or KRas G12C inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, compounds of the invention are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.

[0119] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0120] As used herein, the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0121] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. In one embodiment, a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 100 mg / kg, for example 0.1 to 50 mg / kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt / wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

[0122] The pharmaceutical compositions comprising compounds of the present invention may be used in the methods of use described herein. METHODS OF USE

[0123] In yet another aspect, the invention provides for methods for inhibiting KRas G12S and / or KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12S activity is desired with an effective amount of a compound of Formula (Ia) or (Ib), pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0124] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12S with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12S, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12S. For example, "contacting" a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.

[0125] In one embodiment, a cell in which inhibition of KRas G12S and / or KRas G12C activity is desired is contacted with an effective amount of a compound of Formula (Ia) or (Ib), or pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12S and / or KRas G12C.

[0126] By negatively modulating the activity of KRas G12S and / or KRas G12C, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12S and / or KRas G12C activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to affect the desired negative modulation of KRas G12S and / or KRas G12C. The ability of compounds to bind KRas G12S and / or KRas G12C may be monitored in vitro using well known methods, including those described in Examples A and B below. In addition, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12S and / or KRas G12C activity of the amount of phosphorylated ERK, for example using the method described in Example C below.

[0127] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.

[0128] The compositions and methods provided herein may be used for the treatment of a KRas G12S-associated cancer and / or KRas G12C-associated cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. In one embodiment, the KRas G12S-associated cancer is lung cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer

[0129] The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include but are not limited to tumor types such as astrocytic, breast,cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

[0130] In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In certain embodiments, the cancer is non- small cell lung cancer.

[0131] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti- neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0132] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[0133] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.

[0134] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of KRas G12S and / or KRas G12C.

[0135] Also provided herein is a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12S-associated and / or a KRas G12C-associated disease or disorder.

[0136] Also provided herein is the use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0137] Also provided herein is a use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12S and / or KRas G12C.

[0138] Also provided herein is the use of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12S-associated and / or a KRas G12C-associated disease or disorder.

[0139] Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12S mutation or a KRas G12C mutation (e.g., a KRas G12S-associated cancer or a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0140] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0141] One skilled in the art will further recognize that human clinical trials including first-in- human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts. EXAMPLES

[0142] The compounds of the present invention may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art.

[0143] The following Examples are intended to illustrate further certain embodiments of the invention and are not intended to limit the scope of the invention.Reagent abbreviation: DCM Dichloromethane DMAP 4-Dimethylaminopyridine EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide TFA Trifluoroacetic acid DMF Dimethylformamide HATU Hexafluorophosphate azabenzotriazole tetramethyl uranium (1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5- b]pyridine 4-oxide hexafluorophosphate(V)) DMAc Dimethylacetamide DIEA N,N-Diisopropylethylamine PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate HOBt 1-Hydroxybenzotriazole DMP Dess–Martin periodinane TEA Triethylamine CMPI 2-Chloro-1-methylpyridinium iodide DCC N,N'-Dicyclohexylcarbodiimide EXAMPLE 1(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol- 1-yl)methanone

[0144] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4- yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equiv) and 3- methyl-1H-pyrazole (10.0 mg, 1.5 equiv) in DCM (1 mL) were added DMAP (12.3 mg, 1.2 equiv) and EDCI (19.3 mg, 1.2 equiv). The reaction was stirred at 25 °C for 12 hours. The mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18150 × 25mm × 5µm; A: water (FA), B: ACN, B%: 15%-45% B over 10 min] to afford the title compound (12.1 mg, 22% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.96 (s, 1H), 8.16 (d, J = 2.8 Hz, 1H), 7.54 (dd, J = 5.6, 8.8 Hz, 1H), 7.23-7.12 (m, 2H), 7.09-6.96 (m, 1H), 6.29 (d, J = 2.8 Hz, 1H), 5.44-5.21 (m, 1H), 4.71-4.54 (m, 2H), 4.42-4.23 (m, 2H), 4.01 (dt, J = 5.2, 10.4 Hz, 1H), 3.63-3.11 (m, 6H), 3.08-2.94 (m, 1H), 2.46 (br d, J = 7.6 Hz, 1H), 2.36 (s, 3H), 2.24-1.99 (m, 10H), 0.83-0.74 (m, 3H); LCMS (ESI, M+1): m / z = 686.4. EXAMPLE 23-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonyl)oxazolidin-2-one

[0145] Step A.2-(8-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of 1-bromo-8-fluoronaphthalene (9.00 g, 1.0 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (15.2 g, 1.5 equiv) in dioxane (100 mL) were added potassium acetate (11.8 g, 3.0 equiv) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.93 g, 0.10 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 °C for 1 hour. The mixturewas diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 1 / 1] to afford the title compound (8.50 g, 78% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 8.04 (td, J = 2.4, 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.52 (dt, J = 5.2, 8.0 Hz, 1H), 7.35 (dd, J = 8.0, 12.0 Hz, 1H), 1.36 (s, 12H).

[0146] Step B. 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,2,2-trifluoroethanol (4.36 g, 1.1 equiv) in THF (50 mL) was added t-BuONa (4.19 g, 1.1 equiv) in portions at 25 °C. The reaction was stirred at 25 °C for 1 hour. The mixture was added into a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (10.0 g, 1.0 equiv) in THF (100 mL) at -40 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, Petroleum ether / Ethyl acetate=30 / 1 to 1 / 1] to afford the title compound (7.10 g, 80% yield) as white solid; LCMS (ESI, M+1): m / z =315.0.

[0147] Step C: 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (7.00 g, 1.0 equiv) and 1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethanol (3.13 g, 1.0 equiv) in THF (70 mL) was added Na2CO3(7.04 g, 3.0 equiv). The reaction was stirred at 40 °C for 3 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 0 / 1] to afford the title compound (8.50 g, 83% yield) as white solid; LCMS (ESI, M+1): m / z =421.1.

[0148] step D: 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7-chloro-8-fluoro-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5.00 g, 1.0 equiv) in CPME (5.0 mL) were added 2-(8-fluoro-1-naphthyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (3.23 g, 1.0 equiv), Cs2CO3(23.8 mL, 3.0 equiv) and CataCXium A Pd G3 (865 mg, 0.1 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction wasstirred at 90 °C for 1 hour. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with column chromatography [SiO2, Petroleum ether / Ethyl acetate=10 / 1] to afford the title compound (4.60 g, 67% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.20 (s, 1H), 8.22 - 8.18 (m, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.78-7.73 (m, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.60 (dt, J = 5.2, 8.0 Hz, 1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 5.43-5.31 (m, 2H), 4.18 (s, 2H), 3.01-2.89 (m, 2H), 2.61-2.53 (m, 2H), 1.95-1.87 (m, 2H), 1.84-1.75 (m, 4H), 1.64-1.56 (m, 2H); LCMS (ESI, M+1): m / z =531.4.

[0149] Step E. Tert-butyl-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv) and tert-butyl piperidine-4- carboxylate (627 mg, 3.0 equiv) in DMF (10 mL) were added N-ethyl-N,N-diisopropylamine (1.10 g, 9.0 equiv) and 4Å molecular sieve (75.0 mg). The reaction was stirred at 50 °C for 16 hours. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC [(SiO2, Dichloromethane / Methanol) =12 / 1] to afford the title compound (400 mg, 69% yield) as light yellow solid; LCMS (ESI, M+1): m / z = 616.4.

[0150] Step F. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a solution of tert-butyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (100 mg, 1.0 equiv) in DCM (5.5 mL) was added TFA (1.8 mL) at 0 °C. The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated to afford title compound (90.0 mg, crude) as light yellow oil; LCMS (ESI, M+1): m / z = 560.3.

[0151] Step G. 3-(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonyl)oxazolidin-2-one: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) andoxazolidin-2-one (8.56 mg, 1.1 equiv) in DCM (0.5 mL) were added DMAP (13.6 mg, 1.2 equiv) and EDCI (21.4 mg, 1.2 equiv). The reaction was stirred at 30 °C for 12 hours. The mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10µm; A: water (FA), B: ACN, B%: 22%-52% B over 9 min] and prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10µm; A: water (FA), B: ACN, B%: 20%-50% B over 9 min] to afford the title compound (7.42 mg, 13% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.04 (s, 1H), 7.99 (br d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68-7.58 (m, 2H), 7.45 (dt, J = 4.8, 8.0 Hz, 1H), 7.12 (dd, J = 7.6, 12.8 Hz, 1H), 4.77-4.63 (m, 2H), 4.57-4.43 (m, 4H), 4.07 (t, J = 8.0 Hz, 2H), 4.02-3.91 (m, 1H), 3.60-3.42 (m, 4H), 2.79 (td, J = 6.6, 10.8 Hz, 2H), 2.26 (td, J = 6.4, 12.0 Hz, 2H), 2.19-2.09 (m, 2H), 2.09-1.92 (m, 6H), 1.89-1.77 (m, 2H); LCMS (ESI, M+1): m / z = 629.3. EXAMPLE 31-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(pyridin-2-yl)piperidine-4-carboxamide

[0152] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(pyridin-2-yl)piperidine-4-carboxamide: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equiv) in DMF (2 mL) were added HATU (272 mg, 2 equiv), DIEA (277 mg, 6.0 equiv) and pyridin-2-amine (37 mg, 1.1 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was purified by prep- HPLC [Waters Xbridge 150 × 25mm × 5 µm; A: water (NH4HCO3), B: ACN, B%: 34%-64% B over 9 min] to afford the title compound (7.46 mg, 3.2% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.05 (s, 1H), 8.31 (dd, J = 0.8, 4.8 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.01 (td, J = 1.8, 7.6 Hz, 1H), 7.78-7.71 (m, 2H), 7.68-7.60 (m, 2H), 7.46 (dt, J = 5.2, 7.8 Hz, 1H), 7.17-7.05 (m, 2H), 4.71 (br d, J = 13.6 Hz, 2H), 4.27 (s, 2H), 3.53-3.39 (m, 2H), 3.16 (td, J = 5.2, 10.0 Hz, 2H), 2.77-2.62 (m, 3H), 2.24-2.10 (m, 6H), 1.94-1.87 (m, 4H), 1.74-1.65 (m, 2H); LCMS (ESI, M+1): m / z = 636.3. EXAMPLE 4(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(1H-pyrazol-1- yl)methanone

[0153] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carboxylate: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (1.0 g, 1.0 equiv) and methyl piperidine-4-carboxylate (290 mg, 1.2 equiv) in DMAC (10 mL) was added K3PO4(1.07 g, 3.0 equiv). The reaction was stirred at 60 °C for 0.5 hours. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4and concentrated to afford the title compound (1.2 g, crude) as yellow oil.

[0154] Step B. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate (1.2 g, 1.0 equiv) in MeOH (4.0 mL) was added LiOH•H2O (2 M, 3.78 mL, 4.0 equiv). The reaction was stirred at 20 °C for 0.5 hours. The mixture was filtered and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (0.8 g, 65.8% yield) as white solid; LCMS (ESI, M+1): m / z = 622.3.

[0155] Step C. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4- yl)(1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equiv) and TEA (81.4 mg, 5.0 equiv)in DMF (2.0 mL) were added EDCI (38.5 mg, 1.25 equiv) and HOBt (2.17 mg, 0.10 equiv). The reaction was stirred at 25 °C for 0.5 hours, and then 1H-pyrazole (43.8 mg, 4.0 equiv) was added. The reaction was added stirred at 25 °C for 48 hours. The mixture was filtered and purified with prep-HPLC [column: Waters Xbridge 150 × 25mm × 5µm; A: water (NH4HCO3), B: ACN; B%: 48%-78% over 9 min] twice. The desired fractions were extracted with DCM (3 × 7.0 mL). The combined organic layers were dried over Na2SO4and concentrated to afford the title compound (11.3 mg, 9.89% yield) as a white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.96 (s, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.58-7.50 (m, 1H), 7.22-7.14 (m, 2H), 7.06-6.94 (m, 1H), 6.50 (dd, J = 1.2, 2.8 Hz, 1H), 5.41-5.20 (m, 1H), 4.74-4.53 (m, 2H), 4.44-4.23 (m, 2H), 4.14-3.98 (m, 1H), 3.61-3.10 (m, 5H), 3.08-2.94 (m, 1H), 2.56-2.39 (m, 1H), 2.38-2.27 (m, 1H), 2.26-2.04 (m, 7H), 2.00-1.89 (m, 3H), 0.82 (br t, J = 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 672.3. EXAMPLE 52,6-difluorophenyl (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6- carboxylate EXAMPLE 62,6-difluorophenyl (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6- carboxylate

[0156] Step A. 2,6-difluorophenyl (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.1.1]heptane-6-carboxylate and 2,6-difluorophenyl (1R,5S,6r)-3-(8-fluoro-7-(8- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 3-(8-fluoro-7-(8- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid (150 mg, 1.0 equiv), EDCI (75.5 mg, 1.5 equiv) and DMAP (48.1 mg, 1.5 equiv) in DCM (2 mL) was added 4-fluorophenol (68.3 mg, 2.0 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated. The residue was diluted with H2O (2 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: YMC-Actus Triart C18150 × 30 mm × 7 µm; A: water (FA), B: ACN; B%:20%-50% B over 10 min] and lyophilized to afford to afford the two isomers.

[0157] 2,6-difluorophenyl (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6- carboxylate (Example 5, , 2.61 mg, 1.3% yield) as yellow-white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.48-9.43 (m, 1H), 8.02-7.98 (m, 1H), 7.77-7.73 (m, 1H), 7.66-7.60 (m, 2H), 7.48-7.41 (m, 1H), 7.24-7.17 (m, 1H), 7.12 (dd, J = 7.6, 12.8 Hz, 1H), 7.02 (s, 2H), 4.66- 4.56 (m, 2H), 4.50 (s, 4H), 3.75-3.63 (m, 2H), 3.23 (br d, J = 6.0 Hz, 2H), 3.08 (d, J = 5.6 Hz, 1H), 2.96-2.89 (m, 2H), 2.36 (br dd, J = 6.4, 12.8 Hz, 2H), 2.21-2.13 (m, 2H), 2.13-2.04 (m, 3H), 1.95 (br dd, J = 6.8, 13.2 Hz, 2H), 1.66 (br dd, J = 6.0, 10.0 Hz, 1H); LCMS (ESI, M+1): m / z = 684.4.

[0158] 2,6-difluorophenyl (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6- carboxylate (Example 6, , 3.51 mg, 1.8% yield) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.50-9.43 (m, 1H), 8.03-7.93 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.66-7.59 (m, 2H), 7.48-7.41 (m, 1H), 7.17-7.07 (m, 2H), 6.95-6.86 (m, 2H), 4.82-4.66 (m, 2H), 4.63-4.53 (m, 2H), 4.37-4.26 (m, 2H), 3.74-3.59 (m, 2H), 3.58-3.48 (m, 1H), 3.23-3.13 (m, 2H), 2.99-2.86 (m, 2H), 2.37-2.33 (m, 2H), 2.16-2.09 (m, 2H), 2.09-2.04 (m, 2H), 2.01 (br d, J = 4.0 Hz, 1H), 1.92 (br dd, J = 6.8, 13.2 Hz, 2H), 1.67 (d, J = 10.0 Hz, 1H); LCMS (ESI, M+1): m / z = 684.4. EXAMPLE 74-fluorophenyl (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylateEXAMPLE 84-fluorophenyl (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate

[0159] Step A. methyl 3-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of 3-(tert-butyl) 6- methyl 3-azabicyclo[3.1.1]heptane-3,6-dicarboxylate (950 mg, 1.0 equiv) in MeCN (10 mL) was added HCl•dioxane (10 mL，4M). The reaction was stirred at 0 °C for 1 hour. The mixture was concentrated and diluted with MeOH (10 mL). The mixture was adjusted pH to 7 by NaHCO3 solid, filtered and concentrated to afford the title compound (570 mg, 99 % yield) as white solid;

[0160] Step B. methyl 3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.95 g, 1.0 equiv), methyl 3- azabicyclo[3.1.1]heptane-6-carboxylate (570 mg, 1.0 equiv) in DMAc (10 mL) was added K3PO4 (2.34 g, 3.0 equiv). The reaction was stirred at 60 °C for 12 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (750 mg, 35% yield) as yellow solid; LCMS (ESI, M+1): m / z = 586.4;

[0161] Step C. 3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid: To a solution of methyl 3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate (100 mg, 1.0 equiv) in MeOH (1 mL) and H2O (1 mL) was added LiOH•H2O (179 mg, 25 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and adjust to pH=7 with HCl (4 M). The mixture was filtered to afford the title compound (70.0 mg, 72% yield) as yellow solid; LCMS (ESI, M+1): m / z = 572.4;

[0162] Step D.4-fluorophenyl (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6- carboxylate and 4-fluorophenyl (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6- carboxylic acid (35 mg, 1.0 equiv), EDCI (17.6 mg, 1.5 equiv) and DMAP (11.2 mg, 1.5 equiv) in DCM (1 mL) was added 4-fluorophenol (13.7 mg, 2.0 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated. The residue was diluted with H2O (2 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, concentrated and purified with prep-HPLC [column: Welch Xtimate C18 150 × 25 mm × 5 µm; A: water (FA), B: ACN; B%:30%-50% B over 10 min] to afford two isomers.

[0163] 4-fluorophenyl (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]heptane-6- carboxylate (Example 7, , 2.05 mg, 4.7% yield) as yellow-white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.50-9.43 (m, 1H), 8.04-7.96 (m, 1H), 7.78-7.72 (m, 1H), 7.67-7.58 (m, 2H), 7.50-7.42 (m, 1H), 7.16-7.11 (m, 3H), 7.10 (d, J = 2.4 Hz, 2H), 4.90-4.81 (m, 2H), 4.57-4.47 (m, 4H), 3.96-3.84 (m, 2H), 3.24-3.15 (m, 2H), 3.03-2.93 (m, 3H), 2.86-2.78 (m, 1H), 2.51-2.41 (m, 2H), 2.33-2.21 (m, 2H), 2.20-2.10 (m, 2H), 2.09-2.00 (m, 2H), 1.29-1.24 (m, 1H); LCMS (ESI, M+1): m / z = 666.4

[0164] 4-fluorophenyl (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.1.1]heptane-6- carboxylate (Example 8, , 2.38 mg, 5.5% yield) as off-white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.49-9.43 (m, 1H), 8.03-7.96 (m, 1H), 7.77-7.71 (m, 1H), 7.67-7.57 (m, 2H), 7.49-7.41 (m, 1H), 7.11 (dd, J = 7.6, 12.8 Hz, 1H), 7.00 (s, 2H), 6.93-6.84 (m, 2H), 4.91- 4.62 (m, 4H), 4.44-4.26 (m, 2H), 3.98-3.72 (m, 2H), 3.47 (br d, J = 2.8 Hz, 1H), 3.23-3.07 (m, 2H), 3.02-2.84 (m, 2H), 2.44-2.29 (m, 3H), 2.26-2.15 (m, 2H), 2.14-2.05 (m, 2H), 2.04-1.91 (m, 2H), 1.66 (br s, 1H); LCMS (ESI, M+1): m / z = 666.4. EXAMPLE 9(3,5-dimethyl-1H-pyrazol-1-yl)(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanone

[0165] Step A. (3,5-dimethyl-1H-pyrazol-1-yl)(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4- yl)methanone: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equiv) in DCM (0.5 mL) were added 3,5-dimethyl-1H-pyrazole (25.8 mg, 3.0 equiv), EDCI (25.7 mg, 1.5 equiv) and DMAP (16.4 mg,, 1.5 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was diluted with water (1 mL), neutralized with solid NaHCO3and extracted with ethyl acetate (2 × 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 30%-60% over 7 min] to afford the title compound (16.4 mg, 28% yield, HCOOH salt) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.11 (s, 1H), 8.19 (br d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.78-7.72 (m, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.59 (dt, J = 5.2, 8.0 Hz, 1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 6.23 (s, 1H), 4.58 (br d, J = 13.2 Hz, 2H), 4.08 (s, 2H), 4.07-3.99 (m, 1H), 3.57 (br t, J = 12.8 Hz, 2H), 2.98-2.90 (m, 2H), 2.59- 2.53 (m, 2H), 2.49 (s, 3H), 2.23 (s, 3H), 2.18-2.09 (m, 2H), 1.99-1.87 (m, 4H), 1.85-1.71 (m, 4H), 1.63-1.54 (m, 2H); LCMS (ESI, M+1): m / z = 638.4. EXAMPLE 10(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0166] Step A. (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equiv) in DCM (0.5 mL) were added 5-methyl-1H-pyrazole (22.0 mg, 3.0 equiv), EDCI (25.7 mg, 1.5 equiv) and DMAP (16.4 mg, 1.5 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was diluted with water (1 mL), neutralized with solid NaHCO3 and extracted with ethyl acetate (2 × 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 28%-58% B over 7 min] to afford the title compound (15.1 mg, 27% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.12 (s, 1H), 8.32 (d, J = 2.8 Hz, 1H), 8.19 (br d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.79-7.72 (m, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.59 (dt, J = 5.2, 7.6 Hz, 1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 4.59 (br d, J = 13.2 Hz, 2H), 4.08 (s, 2H), 4.05-3.95 (m, 1H), 3.59 (br t, J = 12.8 Hz, 2H), 2.99-2.88 (m, 2H), 2.58-2.53 (m, 2H), 2.31 (s, 3H), 2.19-2.11 (m, 2H), 2.01-1.86 (m, 4H), 1.86-1.71 (m, 4H), 1.63-1.53 (m, 2H); LCMS (ESI, M+1): m / z = 624.4. EXAMPLE 11(1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(1H-pyrazol-1-yl)methanone

[0167] Step A. (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(1H-pyrazol-1-yl)methanone: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (150 mg, 1.0 equiv) in DCM (1.5 mL) were added 1H-pyrazole (54.7 mg, 3.0 equiv), EDCI (77.1 mg, 1.5 equiv) and DMAP (49.1 mg, 1.5 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was diluted with water (5 mL) and extracted with DCM (10 mL). The combined organic layer was dried over sodium sulfate, concentrated under and purified by prep-HPLC. and purified with prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 18%-48% B over 10min] to afford the title compound (14.4 mg, 8% yield) as white solid;1H NMR (400 MHz, CDCl3) δ = 9.10 (s, 1H), 8.29 (d, J = 4.8 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.77-7.73 (m, 2H), 7.63-7.59 (m, 3H), 7.50-7.40 (m, 1H), 7.14-7.09 (m, 1H), 6.52 (s, 1H), 4.76-4.72 (m, 2H), 4.29 (s, 2H), 4.15- 4.00 (m, 1H), 3.51 (br t, J = 12.0 Hz, 2H), 3.20-3.18 (m, 2H), 2.69-2.68 (m, 2H), 2.23-2.22 (m, 2H), 2.16-2.12 (m, 4H), 1.93-1.88 (m, 4H), 1.71-1.60 (m, 2H); LCMS (ESI, M+1): m / z = 610.4. EXAMPLE 122,4,6-trifluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0168] Step A. methyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.00 g, 1.0 equiv) in DMAC (20 mL) were added K3PO4 (2.40 g, 3.0 equiv) and methyl piperidine-4-carboxylate (1.62 g, 3.0 equiv). The reaction was stirred at 60 °C for 1 hour. The mixture was filtered, concentrated and purified by reversed phase flash[C18, 0.1% formic acid condition] to afford the title compound (2.07 g, 92% yield) as white solid; LCMS (ESI, M+1): m / z = 574.3.

[0169] Step B. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a solution of methyl 1- (8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (2.07 g, 1.0 equiv) in MeOH (21 mL) was added LiOH•H2O (757 mg, 5.0 equiv) and H2O (7 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and purified by reversed phase flash [C18, 0.1% formic acid condition] to afford the title compound (1.49 g, 68% yield) as white solid; LCMS (ESI, M+1): m / z = 560.3.

[0170] Step C. 2,4,6-trifluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (80.0 mg, 1.0 equiv) and 2,4,6-trifluorophenol (63.5 mg, 3.0 equiv) in DCM (2 mL) were added DMAP (26.2 mg, 1.5 equiv) and EDCI (41.1 mg, 1.5 equiv). The reaction was stirred at 30°C for 1 hour. The mixture was concentrated and purified by prep-HPLC [column: Welch Ultimate XB-SiOH 250 × 50mm × 10µm; A: Hexane, B: EtOH, B%: 5%-45% B over 15 min] and prep-HPLC [column: Welch Xtimate C18 150 × 25mm × 5µm; A: water (FA), B: ACN, B%: 25%-55% B over 10 min] to afford the title compound (3.52 mg, 3.3% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.06 (s, 1H), 8.01 (br d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69-7.57 (m, 2H), 7.47 (dt, J = 4.8, 8.0 Hz, 1H), 7.14 (dd, J = 7.6, 12.8 Hz, 1H), 6.90-6.74 (m, 2H), 4.55 (br dd, J = 4.0, 13.2 Hz, 2H), 4.36 (s, 2H), 3.77-3.57 (m, 2H), 3.34-3.22 (m, 2H), 3.20-3.05 (m, 1H), 2.83-2.64 (m, 2H), 2.44- 2.28 (m, 2H), 2.27-2.09 (m, 4H), 2.07-1.87 (m, 4H), 1.83-1.66 (m, 2H); LCMS (ESI, M+1): m / z = 690.3. EXAMPLE 132,4-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0171] Step A. 2,4-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 2,4-difluorophenol (34.9 mg, 3.0 equiv) in DCM (1 mL) were added DMAP (16.4 mg, 1.5 equiv) and EDCI (25.7 mg, 1.5 equiv). The reaction was stirred at 30 °C for 1 hour. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were concentrated and purified by prep-TLC (Dichloromethane : Methanol = 8 / 1) and prep- HPLC [column: Welch Xtimate C18150 × 25mm × 5µm; A: water (FA), B: ACN, B%: 23%-53% B over 10 min] to afford the title compound (2.19 mg, 3.6% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.05 (s, 1H), 8.05-7.95 (m, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.68-7.57(m, 2H), 7.50-7.41 (m, 1H), 7.18-7.07 (m, 2H), 7.01-6.84 (m, 2H), 4.55 (br dd, J = 4.4, 9.2 Hz, 2H), 4.39-4.23 (m, 2H), 3.68-3.54 (m, 2H), 3.29-3.01 (m, 3H), 2.77-2.61 (m, 2H), 2.38-2.25 (m, 2H), 2.24-2.07 (m, 4H), 1.96-1.87 (m, 4H), 1.74-1.66 (m, 2H); LCMS (ESI, M+1): m / z = 672.3. EXAMPLE 144-fluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0172] Step A. 4-fluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equiv) and 4- fluorophenol (80.1 mg, 2.0 equiv) in DCM (2 mL) were added DMAP (65.5 mg, 1.5 equiv) andEDCI (103 mg, 1.5 equiv). The reaction was stirred at 30°C for 1 hour. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were concentrated and purified with prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10µm; A: water (FA), B: ACN, B%: 30%-60% B over 9 min], prep-TLC (Dichloromethane : Methanol = 8 / 1) and prep-HPLC [column: Welch Xtimate C18150 × 25mm × 5µm; A: water (FA), B: ACN, B%: 20%-50% B over 10 min] to afford the title compound (2.88 mg, 1.2% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.05 (s, 1H), 8.00 (br d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.68-7.59 (m, 2H), 7.45 (dt, J = 4.8, 8.0 Hz, 1H), 7.13 (br d, J = 12.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 2H), 7.08 (s, 2H), 4.66-4.54 (m, 2H), 4.34 (s, 2H), 3.63-3.49 (m, 2H), 3.32-3.19 (m, 2H), 3.07-2.95 (m, 1H), 2.70 (td, J = 7.2, 10.4 Hz, 2H), 2.30 (br dd, J = 2.8, 13.6 Hz, 2H), 2.22-2.07 (m, 5H), 1.95-1.91 (m, 4H), 1.78-1.69 (m, 2H); LCMS (ESI, M+1): m / z = 654.2. EXAMPLE 151-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbaldehyde

[0173] Step A. 4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- fluoronaphthalen-2-ol: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (200 mg, 1.0 equiv), 4-(dimethoxymethyl)piperidine (161 mg, 3.0 equiv) and 4Å molecular sieve (20 mg) in DMF (1 mL) was added DIEA (131 mg, 3.0 equiv). The reaction was stirred at 60 °C for 2 hours. The mixture was filtered and the filtrate was purified with reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (150 mg, 65% yield) as yellow solid; LCMS (ESI, M+1): m / z = 652.4.

[0174] Step B. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carbaldehyde: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (120 mg, 1 equiv) in DCM (100 μL) was added TFA (420 mg, 20 equiv). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated. The residue was diluted with saturated NaHCO3aqueous solution (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep- HPLC [YMC Triart 30 × 150mm × 7 µm; A: water (FA); B: ACN, B%: 25%-55% over 8 min] and prep-HPLC [C18150 × 30 mm; A: water (FA); B: ACN, B%: 20%-50% over 7 min] to afford the title compound (85.0 mg, 75% yield, HCOOH salt) as white solid;1H NMR (400 MHz, METHANOL-d4) δ 9.09-9.02 (m, 1H), 7.68 (dd, J = 5.6, 8.8 Hz, 1H), 7.33-7.29 (m, 1H), 7.28- 7.21 (m, 1H), 7.08-7.03 (m, 1H), 5.51-5.30 (m, 1H), 4.79-4.68 (m, 2H), 4.51-4.38 (m, 2H), 4.38- 4.32 (m, 1H), 3.61-3.37 (m, 5H), 3.24-3.14 (m, 1H), 2.56-2.33 (m, 3H), 2.29-2.08 (m, 4H), 2.07- 1.88 (m, 4H), 1.69-1.53 (m, 2H), 0.85-0.76 (m, 3H); LCMS (ESI, M+1): m / z = 606.3. EXAMPLE 16methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carboxylate

[0175] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carboxylate: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (100 mg, 1.0 equiv), methyl piperidine-4-carboxylate (48.3 mg, 2.0 equiv) and 4Å molecular sieve (20 mg) in DMSO (1 mL) was added DIEA (65.4 mg, 3.0 equiv). The reaction was stirred at 40 °C for 12 hours. The mixture was filtered and the filtrate was purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] and prep-HPLC [Waters Xbridge 150 × 25mm × 5 μm; A: water (NH4HCO3), B: ACN, B:48%-78% over 9 min] to afford the title compound (22.4 mg, 21% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ 9.04 (s, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 5.40- 5.21 (m, 1H), 4.64-4.53 (m, 2H), 4.35-4.22 (m, 2H), 3.72 (s, 3H), 3.67-3.54 (m, 2H), 3.29-3.16(m, 3H), 3.06-2.97 (m, 1H), 2.91-2.81 (m, 1H), 2.54-2.40 (m, 1H), 2.39-2.09 (m, 6H), 2.04-1.84 (m, 5H), 0.85-0.74 (m, 3H); LCMS (ESI, M+1): m / z = 636.4. EXAMPLE 17(1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbaldehyde

[0176] Step A. (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid: To a mixture of (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (780 mg, 1.0 equiv) and NaOH (221 mg, 1.1 equiv) in H2O (10.0 mL) was added CbzCl (1.07 g, 1.2 equiv) at 0 °C. The reaction was stirred at 0-10 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated and purified with reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (503 mg, 20% yield) as yellow oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 7.37-7.30 (m, 5H), 5.14 (s, 2H), 4.72 (s, 1H), 4.07-3.88 (m, 2H), 3.05-2.91 (m, 2H), 2.69-2.56 (m, 2H), 1.88-1.75 (m, 2H), 1.65-1.45 (m, 2H); LCMS (ESI, M+1): m / z = 290.0

[0177] Step B. benzyl (1R,5S,8r)-8-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a solution of (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (300 mg, 1.0 equiv) in THF (3.00 mL) was added BH3•Me2S (10 M, 3.0 equiv) at 0 °C. The reaction was stirred at 0 °C for 2 hours. The mixture was quenched with MeOH (5.00 mL) and concentrated under vacuum. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated and purified with prep-HPLC [column: YMC-Gel SiL-HG 250 mm × 70 mm × 10 µm; A: Hexane, B: EtOH, B%: 5%-45% over 15 min] to afford the title compound (190 mg, 60% yield) as colorless oil; LCMS (ESI, M+1): m / z = 276.1

[0178] Step C. ((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)methanol: To a solution of benzyl (1R,5S,8r)-8-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (170 mg, 1.0 equiv) in MeOH (5.00 mL) was added Pd / C (20 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2for 3 times. The reaction was stirred under H2(15 Psi) at 30 °C for 2 hours. The mixture was filtered and concentrated to afford the title compound (60 mg, crude) as white solid; LCMS (ESI, M+1): m / z = 142.1

[0179] Step D. ((1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)methanol: To a mixture of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (130 mg, 1.0 equiv) and ((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)methanol (51.9 mg, 1.5 equiv) in DMF (3.00 mL) were added K3PO4 (156 mg, 3.0 equiv) and 4 Å molecular sieve (20 mg). The reaction was stirred at 40 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (45 mg, 30% yield) as white solid; LCMS (ESI, M+1): m / z = 572.4

[0180] Step E. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbaldehyde: To a solution of ((1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)methanol (20.0 mg, 1.0 equiv) in DCM (1.00 mL) was added DMP (22.3 mg, 1.5 equiv) at 0 °C. The reaction was stirred at 0 °C for 2 hours. The mixture was quenched with saturated NaHCO3solution (10.0 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (7.41 mg, 33% yield, CF3COOH salt) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.07 (s, 1H), 8.11 (br d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.74-7.67 (m, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.53 (dt, J = 5.2, 8.0 Hz, 1H), 7.25- 7.14 (m, 1H), 4.83-4.70 (m, 2H), 4.40 (s, 2H), 4.25 (d, J = 8.4 Hz, 1H), 3.68-3.55 (m, 2H), 2.97- 2.84 (m, 2H), 2.50 (br s, 2H), 2.23-2.11 (m, 2H), 2.11-1.93 (m, 5H), 1.92-1.82 (m, 2H), 1.82-1.72 (m, 2H), 1.65-1.52 (m, 2H); LCMS (ESI, M+1): m / z = 570.3. EXAMPLE 182,2,2-trifluoroethyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate

[0181] Step A. 2,2,2-trifluoroethyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equiv) and 2,2,2-trifluoroethanol (25.6 mg, 3.0 equiv) in DCM (1 mL) were added DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 equiv). The reaction was stirred at 30 °C for 2 hours. The reaction was concentrated and purified with prep-HPLC [Phenomenex Luna C18150 × 25mm × 10µm; A: water (TFA); B: ACN; B%: 15%-45% over 9 min]. The desired fraction was collect. The mixture was adjusted to pH=7 with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na2SO4, concentrated and purified with prep-HPLC [ Phenomenex luna C18 150 × 25mm × 10µm;A: water (FA); B: ACN; B%: 28%-58% over 9 min] to afford the title compound (19.1 mg, 31% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.22-9.08 (m, 1H), 8.19 (dd, J = 8.0 Hz, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.81-7.71 (m, 1H), 7.68-7.55 (m, 2H), 7.36-7.27 (dd, J = 7.2, 13.2 Hz, 2H), 4.82 (q, J = 9.2 Hz, 2H), 4.63 (br d, J = 10.0 Hz, 2H), 4.13 (s, 2H), 3.68 (br d, J = 12.8 Hz, 2H), 3.15 (s, 1H), 3.07-2.92 (m, 2H), 2.74 (br s, 2H), 2.67-2.60 (m, 2H), 2.00-1.89 (m, 2H), 1.88-1.74 (m, 4H), 1.74-1.50 (m, 6H); LCMS (ESI, M+1): m / z = 668.4. EXAMPLE 19methyl (1R,5S,8s)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate

[0182] Step A. methyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylic acid (90 mg, 1.0 equiv), 4-hydroxybenzonitrile (36.6 mg, 2.0 equiv) and EDCI (44.2 mg, 1.5 equiv) in DCM (2.00 mL) was added DMAP (28.2 mg, 1.5 equiv). The reaction was stirred at 40 °C for 1 hour. MeOH (1 mL, 160 equiv) was added into the mixture. The reaction was stirred at 60 °C for 2 hours. The mixture wash diluted with water (30 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated and purified with prep-HPLC [column: Welch Ultimate XB-SiOH 250 × 50 × 10 µm; A: Hexane- EtOH ;B:10%-50% over 15 min] to afford the title compound (23.7 mg, 25% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.14-9.07 (m, 1H), 8.18 (br d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.77-7.70 (m, 1H), 7.65-7.62 (m, 1H), 7.58 (dt, J = 5.2, 8.0 Hz, 1H), 7.31 (dd, J = 7.6, 13.2 Hz, 1H), 4.59 (br d, J = 12.4 Hz, 2H), 4.07 (s, 2H), 3.64 (s, 4H), 3.62 (s, 1H), 2.99-2.91(m, 3H), 2.70 (br s, 2H), 2.61-2.52 (m, 2H), 1.96-1.86 (m, 2H), 1.85-1.71 (m, 4H), 1.70-1.64 (m, 2H), 1.59 (br dd, J = 7.2, 12.4 Hz, 2H), 1.55-1.47 (m, 2H); LCMS (ESI, M+1): m / z = 600.3. EXAMPLE 204-cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate

[0183] Step A. 4-cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylic acid (50 mg, 1.0 equiv), 4-hydroxybenzonitrile (30.5 mg, 3.0 equiv) and DMAP (15.6 mg, 1.5 equiv) in DCM (1.00 mL) was added EDCI (24.6 mg, 1.5 equiv). The reaction was stirred at 10 °C for 16 hours. The mixture was concentrated and purified with prep-HPLC [column: Phenomenex Luna C18150 × 25 mm × 10 µm; A: water (TFA), B: ACN, B%: 30%-60% over 9min] to afford the title compound (25.5 mg, 42% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.18 (br d, J = 8.4 Hz, 1H), 7.99-7.90 (m, 3H), 7.78-7.70 (m, 1H), 7.66-7.62 (m, 1H), 7.61-7.55 (m, 1H), 7.45-7.39 (m, 2H), 7.31 (dd, J = 7.2, 13.2 Hz, 1H), 4.66 (br d, J = 12.0 Hz, 2H), 4.07 (s, 2H), 3.71 (br d, J = 12.4 Hz, 2H), 2.93 (td, J = 5.2, 10.4 Hz, 2H), 2.87 (br s, 2H), 2.59-2.51 (m, 3H), 1.96-1.86 (m, 2H), 1.85-1.70 (m, 6H), 1.67-1.52 (m, 4H); LCMS (ESI, M+1): m / z = 687.3. EXAMPLE 212-cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate

[0184] Step A. 2-cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equiv) and 2-hydroxybenzonitrile (30.5 mg, 3.0 equiv) in DCM (1 mL) were added DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 equiv). The reaction was stirred at 30 °C for 2 hours. The mixture was concentrated and purified with prep-HPLC[ Phenomenex Luna C18150 × 25mm × 10µm; A: water (TFA); B: ACN; B%: 32%-62% over 9 min], followed by prep-HPLC [ Phenomenex luna C18150 × 25mm × 10µm;A: water (FA); B: ACN; B%: 33%- 53% over 10 min] to afford the title compound (11.0 mg, 18% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.20 (s, 1H), 8.19 (br d, J = 8.8 Hz, 1H), 8.01-7.92 (m, 2H), 7.83 (m, 1H), 7.78-7.71 (t, J = 7.6 Hz, 1H), 7.68-7.56 (m, 2H), 7.55-7.46 (m, 2H), 7.32 (dd, J = 7.2, 13.2 Hz, 1H), 4.89-4.59 (m, 2H), 4.53-4.32 (m, 2H), 3.78 (br t, J = 12.0 Hz, 2H), 3.50-3.36 (m, 3H), 3.13- 2.87 (m, 4H), 2.14-2.06 (m, 2H), 2.04-1.81 (m, 8H), 1.68-1.50 (m, 2H); LCMS (ESI, M+1): m / z = 687.3. EXAMPLE 223-cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate

[0185] Step A. 3-cyanophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylic acid (50.0 mg, 1.0 equiv) and 3-hydroxybenzonitrile (30.5 mg, 3.0 equiv) in DCM (1 mL) were added DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 equiv). The reaction was stirred at 30 °C for 2 hours. The mixture was concentrated and purified with prep-HPLC[ Phenomenex Luna C18150 × 25mm × 10µm; A: water (TFA); B: ACN; B%: 30%-60% over 9 min] and prep- HPLC [ Phenomenex luna C18150 × 25mm × 10µm;A: water (FA); B: ACN; B%: 25%-55% over 10 min], and then followed by prep-HPLC [ YMC-Actus Triart C18150 × 30mm × 7µm;A: water (FA); B: ACN; B%: 30%-60% over 10 min] to afford the title compound (14.5 mg, 24% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.18 (br d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.84-7.71 (m, 3H), 7.69-7.62 (m, 2H), 7.61-7.53 (m, 2H), 7.32 (dd, J = 7.2, 13.2 Hz, 1H), 4.66 (br d, J = 10.8 Hz, 2H), 4.10 (s, 2H), 3.72 (br d, J = 12.4 Hz, 2H), 3.30 (s, 1H), 3.01- 2.92 (m, 2H), 2.87 (br s, 2H), 2.58 (td, J = 6.8, 9.8 Hz, 2H), 1.91 (m, 2H), 1.87-1.73 (m, 6H), 1.66- 1.55 (m, 4H); LCMS (ESI, M+1): m / z = 687.3. EXAMPLE 233,4-difluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate

[0186] Step A. 3,4-difluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octane-8-carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (110 mg, 1.0 equiv), 3,4-difluorophenol (48.9 mg, 2.0 equiv) and DMAP (34.4 mg, 1.5 equiv) in DCM (1.00 mL) was added EDCI (54.0 mg, 1.5 equiv). The reaction was stirred at 40 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified with prep-TLC (Dichloromethane: Methanol = 8 / 1), followed by prep-HPLC [column: YMC Triart C18150 × 25 mm × 5 µm; A: water (FA), B: ACN,B%:32%-62% over 2 min]. to afford the title compound (2.90 mg, 2% yield, HCOOH salt) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.06 (s, 1H), 8.00 (br d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.67-7.58 (m, 2H), 7.50-7.42 (m, 1H), 7.24-7.17 (m, 1H), 7.17-7.09 (m, 1H), 7.03-6.95 (m, 1H), 6.88-6.82 (m, 1H), 4.91-4.80 (m, 1H), 4.80-4.71 (m, 1H), 4.28 (br s, 2H), 3.67- 3.51 (m, 2H), 3.31-3.14 (m, 2H), 3.04 (s, 1H), 2.97-2.86 (m, 2H), 2.77-2.61 (m, 2H), 2.22-2.10 (m, 2H), 1.99-1.88 (m, 6H), 1.80-1.67 (m, 4H); LCMS (ESI, M+1): m / z = 698.3. EXAMPLE 242,6-difluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate

[0187] Step A. 2,6-difluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octane-8-carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equiv), 2,6-difluorophenol (33.3 mg, 3.0 equiv) and DMAP (15.6 mg, 1.5 equiv) in DCM (1.00 mL) was added EDCI (24.5 mg, 1.5 equiv). The reaction was stirred at 10 °C for 4 hours. The mixture was concentrated and purified with prep-HPLC [column: Phenomenex Luna C18150 × 25 mm × 10 µm; A: water (TFA), B: ACN, B%: 65% over 9 min] to afford the title compound (8.80 mg, 17% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.16 (s, 1H), 8.13 (br d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.76-7.68 (m, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.54 (dt, J = 5.2, 8.0 Hz, 1H), 7.32 (tt, J = 6.0, 8.4 Hz, 1H), 7.20 (dd, J = 7.6, 13.2 Hz, 1H), 7.15-7.08 (m, 2H), 4.89 (br s, 2H), 4.68 (s, 2H), 3.82 (br d, J = 12.4 Hz, 2H), 3.76-3.65 (m, 2H), 3.41 (s, 1H), 3.30-3.26 (m, 2H), 2.98 (br s, 2H), 2.42-2.32 (m, 2H), 2.30-2.07 (m, 6H), 2.03-1.92 (m, 2H), 1.76-1.65 (m, 2H); LCMS (ESI, M+1): m / z = 698.5. EXAMPLE 252-fluorophenyl (1R,5S,8s)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate

[0188] Step A.2-fluorophenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylic acid (50.0 mg, 1.0 equiv), 2-fluorophenol (28.7 mg, 3.0 equiv) and DMAP (15.6 mg, 1.5 equiv) in DCM (1.00 mL) was added EDCI (24.5 mg, 1.5 equiv). The reaction was stirred at 10 °C for 4 hours. The mixture was concentrated and purified with prep-HPLC [column: Phenomenex Luna C18150 × 25 mm × 10 µm; A: water (TFA), B: ACN, B%: 36%-66% over 9 min] to afford the title compound (8.88 mg, 17% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.16 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.75-7.68 (m, 1H), 7.62 (dd, J = 1.2, 7.2 Hz, 1H), 7.54 (dt, J = 5.2, 8.0 Hz, 1H), 7.33-7.23 (m, 2H), 7.23-7.17 (m, 3H), 4.91-4.86 (m, 2H), 4.68 (s, 2H), 3.81 (br d, J = 12.8 Hz, 2H), 3.76-3.66 (m, 2H), 3.34 (s, 1H), 3.30-3.26 (m, 2H), 2.97 (br s, 2H), 2.41-2.31 (m, 2H), 2.29-2.17 (m, 3H), 2.17-2.07 (m, 3H), 2.02-1.94 (m, 2H), 1.73-1.65 (m, 2H); LCMS (ESI, M+1): m / z = 680.5. EXAMPLE 26phenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate

[0189] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid: To a mixture of (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (1.01 g, 2.0 equiv, HCl), K3PO4(1.68 g, 3.0 equiv) and 4Å molecular sieve (50.0 mg) in DMF (20.0 mL) was added 8-fluoro- 7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.40 g, 1.0 equiv). The reaction was stirred at 60 °C for 2 hours. The mixture was filtered and the filtrate was purified with reversed phase flash chromatography [C18, 0.1 % NH3•H2O condition] to afford the title compound (1.1 g, 69% yield) as brown solid; LCMS (ESI, M+1): m / z = 586.4.

[0190] Step B. phenyl (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate: To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (50.0 mg, 1.0 equiv), phenol (24.1 mg, 3.0 equiv) and DMAP (15.6 mg, 1.5 equiv) in DCM (1.00 mL) was added EDCI (24.5 mg, 1.5 equiv). The reaction was stirred at 10 °C for 4 hours. The mixture was concentrated and purified with prep-HPLC [column: Phenomenex Luna C18150 × 25 mm × 10 µm; A: water (TFA), B: ACN, B%: 35%-65% over 9 min] to afford the title compound (10.0 mg, 18% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.15 (s, 1H), 8.13 (br d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.74-7.68 (m, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.54 (dt, J = 5.2, 8.0 Hz, 1H), 7.45-7.38 (m, 2H), 7.29-7.24 (m, 1H), 7.20 (dd, J = 7.6, 12.8 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 4.90-4.86 (m, 2H), 4.62 (s, 2H), 3.79 (br d, J = 12.8 Hz, 2H), 3.66-3.56 (m, 2H), 3.28 (s, 1H), 3.25-3.17 (m, 2H), 2.95 (br s, 2H), 2.37-2.27 (m, 2H), 2.25-2.01 (m, 6H), 1.99-1.90 (m, 2H), 1.73-1.63 (m, 2H); LCMS (ESI, M+1): m / z = 662.6.2-cyanophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0191] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8-fluoro-7- (8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg) in DMF (3.0 mL) were added K3PO4 (600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z =560.3.

[0192] Step B. 2-cyanophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a mixture of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 2-hydroxybenzonitrile (31.9 mg, 3.0 equiv) in DCM (2.00 mL) were added DMAP (16.4 mg, 1.5 equiv) and EDCI (25.7 mg, 1.5 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified with prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water(FA)-ACN];gradient:37%-67% B over 9 min] to afford the title compound (9.96 mg, 14.6% yield) as off-white solid;1H NMR (400 MHz, DMSO-d6) δ = 10.26 (br s, 1H), 9.19 (s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.96 (t, J = 8.4 Hz, 2H), 7.83 (t, J = 8.0 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.60 (br d, J = 5.2 Hz, 1H), 7.54-7.49 (m, 2H), 7.32 (dd, J = 7.6, 13.1 Hz, 1H), 4.58 (s, 4H), 3.73-3.64 (m, 2H), 3.52 (br dd, J = 5.6, 11.6 Hz, 2H), 3.26-3.18 (m, 2H), 2.33- 2.27 (m, 2H), 2.19 (br dd, J = 5.6, 11.6 Hz, 2H), 2.10 (br d, J = 6.4 Hz, 2H), 2.07 - 1.94 (m, 7H); LCMS (ESI, M+1): m / z =661.3. EXAMPLE 283-cyanophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0193] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8-fluoro-7- (8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg) in DMF (3.00 mL) were added K3PO4(600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281 mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z =560.3.

[0194] Step B. 3-cyanophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a mixture of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 3-hydroxybenzonitrile (31.9 mg, 3.0 equiv) in DCM (2.00 mL) were added DMAP (16.4 mg, 1.5 equiv) and EDCI (25.7 mg, 1.5 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18 150 × 25mm × 10um; mobile phase: [water(FA)-ACN];gradient:25%-55% B over 10 min] and purified by prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water(FA)-ACN]; gradient:37%-67% B over 9 min] to afford the title compound (7.3 mg, 11% yield) as a yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 10.23 (br s, 1H), 9.18 (s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81-7.73 (m, 3H), 7.70-7.63 (m, 2H), 7.62-7.54 (m, 2H), 7.32 (s, 1H), 4.57 (s, 2H), 3.28-3.16 (m, 4H), 2.27-1.97 (m, 13H), 1.23 (br s, 2H), 1.05 (t, J = 7.2 Hz, 2H); LCMS (ESI, M+1): m / z =661.4. EXAMPLE 294-cyanophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0195] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8-fluoro-7- (8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg) in DMF (3.0 mL) were added K3PO4 (600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281 mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as white solid; LCMS (ESI, M+1): m / z =560.3

[0196] Step B. 4-cyanophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a mixture of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 4-hydroxybenzonitrile (31.9 mg, 3.0 equiv) in DCM (2.00 mL) were added DMAP (16.4 mg, 1.5 equiv) and EDCI (25.7 mg, 1.5 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified with prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water(FA)-ACN];gradient:36%-66% B over 9 min] to afford the title compound (20.3 mg, 33% yield) as off-white solid;1H NMR (400 MHz, DMSO-d6) δ = 10.24 (br s, 1H), 9.18 (s, 1H), 8.20 (br d, J = 8.8 Hz, 1H), 7.98-7.93 (m, 3H), 7.75 (d, J = 8.0 Hz, 1H), 7.66-7.57 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 7.6, 13.1 Hz, 1H), 4.60-4.53 (m, 4H), 3.69-3.45 (m, 4H), 2.33-2.22 (m, 3H), 2.18 (br dd, J = 5.6, 11.4 Hz, 2H), 2.10 (br d, J = 6.4 Hz, 2H), 2.07-1.93 (m, 8H); LCMS (ESI, M+1): m / z =661.3. EXAMPLE 302,6-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0197] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8-fluoro-7- (8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg) in DMF (3.0 mL) were added K3PO4 (600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281 mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as white solid; LCMS (ESI, M+1): m / z =560.3.

[0198] Step B. 2,6-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a mixture of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 2,6-difluorophenol (34.8 mg, 3.0 equiv) in DCM (2.0 mL) were added DMAP (16.4 mg, 1.5 equiv) and EDCI (25.7 mg, 1.5 equiv). The reaction was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified with prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water(FA)-ACN];gradient:27%-57% B over 10 min] and prep-HPLC [column: Phenomenex luna C18150 × 40mm × 15um;mobile phase: [water(TFA)-ACN];gradient:35%-65% B over 10 min] to afford the title compound (5.6 mg, 9% yield) as brown solid;1H NMR (400 MHz, DMSO-d6) δ = 10.21 (br s, 1H), 9.19 (s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.67-7.56 (m, 2H), 7.45-7.37 (m, 1H), 7.36-7.28 (m, 3H), 4.61-4.51 (m, 4H), 3.43 (s, 2H), 3.22 (br dd, J = 4.4, 11.2 Hz, 2H), 2.34-2.23 (m, 3H), 2.18 (br dd, J = 6.0, 11.6 Hz, 2H), 2.15- 2.08 (m, 2H), 2.04-1.95 (m, 6H), 1.07-1.03 (m, 2H); LCMS (ESI, M+1): m / z =672.3. EXAMPLE 312,2,2-trifluoroethyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0199] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8-fluoro-7- (8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg)in DMF (3.00 mL) were added K3PO4(600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281 mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as white solid; LCMS (ESI, M+1): m / z =560.3.

[0200] Step B. 2,2,2-trifluoroethyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a mixture of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 2,2,2-trifluoroethanol (26.8 mg, 3.0 equiv) in DCM (2.0 mL) were added DMAP (16.37 mg, 1.5 equiv) and EDCI (25.69 mg, 1.5 equiv). The reaction was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10um; mobile phase:[water(FA)-ACN];gradient:24%-54% B over 10 min] to afford the title compound (16.7 mg, 28% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.25 (s, 1H), 8.18 (br d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.79-7.70 (m, 1H), 7.66-7.54 (m, 2H), 7.31 (dd, J = 7.6, 13.2 Hz, 1H), 4.80 (q, J = 9.2 Hz, 2H), 4.46 (br d, J = 13.2 Hz, 2H), 4.08 (s, 2H), 3.52 (br t, J = 12.0 Hz, 2H), 2.97 (br s, 3H), 2.61-2.52 (m, 2H), 2.17-2.03 (m, 2H), 1.95-1.73 (m, 8H), 1.65-1.54 (m, 2H); LCMS (ESI, M+1): m / z =642.3. EXAMPLE 32pyridin-3-yl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0201] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8-fluoro-7- (8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg) in DMF (3.0 mL) were added K3PO4(600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281 mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers weredried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as white solid; LCMS (ESI, M+1): m / z =560.3

[0202] Step B. pyridin-3-yl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin- 7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a mixture of 1-(8-fluoro- 7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and pyridin-3-ol (25.49 mg, 3.0 equiv) in DCM (2.0 mL) were added DMAP (16.4 mg, 1.5 equiv) and EDCI (25.7 mg, 1.5 equiv). The reaction was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18 150 × 25mm × 10um; mobile phase: [water(FA)- ACN];gradient:28%-58% B over 10 min] to afford the title compound (27.4 mg, 47% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.55-8.45 (m, 2H), 8.20 (br d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.79-7.73 (m, 1H), 7.72-7.56 (m, 4H), 7.52 (dd, J = 4.8, 8.4 Hz, 1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 4.60-4.54 (m, 4H), 3.66 (br d, J = 13.2 Hz, 2H), 3.52 (br d, J = 5.6 Hz, 2H), 2.27 (br d, J = 11.0 Hz, 3H), 2.18 (br dd, J = 5.6, 11.2 Hz, 2H), 2.10 (br d, J = 6.4 Hz, 2H), 2.06-1.97 (m, 7H); LCMS (ESI, M+1): m / z =637.3. EXAMPLE 333,5-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0203] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8- fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg) in DMF (3.0 mL) were added K3PO4 (600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281 mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as white solid; LCMS (ESI, M+1): m / z =560.3

[0204] Step B.3,5-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 3,5-difluorophenol (34.9 mg, 3.0 equiv) in DCM (2.00 mL) were added DMAP (16.37 mg, 1.5 equiv) and EDCI (25.69 mg, 1.5 equiv). The reaction was stirred at 25 °C for 4 hours The mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10um;mobile phase: [water(FA)-ACN];gradient:30%-60% B over 10 min] to afford the title compound (8.30 mg, 14% yield) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 9.11 (s, 1H), 8.31 (s, 1H), 8.18 (br d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.78-7.70 (m, 1H), 7.65-7.56 (m, 2H), 7.31 (dd, J = 7.6, 13.2 Hz, 1H), 7.26-7.18 (m, 1H), 7.09 (dd, J = 2.0, 7.6 Hz, 2H), 4.49 (br d, J = 13.2 Hz, 2H), 4.08 (s, 2H), 3.64-3.57 (m, 2H), 3.19-3.10 (m, 2H), 2.96-2.91 (m, 2H), 2.21 (br dd, J = 3.2, 13.2 Hz, 2H), 2.05-1.97 (m, 2H), 1.93-1.87 (m, 2H), 1.78 (td, J = 6.0, 12.0 Hz, 4H), 1.59 (br dd, J = 7.6, 12.0 Hz, 2H), 1.23 (br s, 1H); LCMS (ESI, M+1): m / z =672.3.EXAMPLE 342,3-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0205] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8-fluoro-7- (8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg) in DMF (3.00 mL) were added K3PO4 (600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281 mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as white solid; LCMS (ESI, M+1): m / z =560.3.

[0206] Step B. 2,3-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equiv) and 2,3-difluorophenol (34.8 mg,3.0 equiv) in dichloromethane (2.00 mL) were added 4-dimethylaminopyridine (16.4 mg, 1.5 equiv) and EDCI (25.7 mg, 1.5 equiv). The mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified with prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10 um; mobile phase: [water(FA)-ACN]; gradient: 28%-58% B over 10 min] to afford the title compound (14.3 mg, 23% yield) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 9.12 (s, 1H), 8.29 (s, 1H), 8.18 (br d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.78-7.71 (m, 1H), 7.66-7.56 (m, 2H), 7.48-7.36 (m, 1H), 7.35-7.26 (m, 2H), 7.22 (br dd, J = 1.6, 6.8 Hz, 1H), 4.50 (br d, J = 13.6 Hz, 2H), 4.08 (s, 2H), 3.64-3.56 (m, 2H), 3.26-3.21 (m, 1H), 2.97-2.91 (m, 2H), 2.24 (br d, J = 10.4 Hz, 2H), 2.09-1.72 (m, 10H), 1.59 (br dd, J = 7.6, 12.0 Hz, 2H); LCMS (ESI, M+1): m / z =672.3.2-fluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0207] Step A. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: To a mixture of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv) and 4Å molecular sieve (100 mg) in DMF (3.00 mL) were added K3PO4(600 mg, 5.0 equiv) and piperidine-4-carboxylic acid (281 mg, 3.0 equiv, HCl). The reaction was stirred at 60 °C for 1.5 hours. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by prep-TLC [petroleum ether / ethyl acetate=3 / 1] to afford the title compound (250 mg, 72% yield) as white solid; LCMS (ESI, M+1): m / z =560.3.

[0208] Step B. 2-fluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 2- fluorophenol (30.0 mg, 3.0 equiv) in dichloromethane (2.0 mL) were added DMAP (16.4 mg, 1.5 equiv) and EDCI (25.7 mg, 1.5 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18250 × 50 mm × 15um; mobile phase: [water(FA)-ACN]; gradient:38%-68% B over 9 min] to afford the title compound (11.2 mg, 19% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.12 (s, 1H), 8.35 (s, 1H), 8.18 (br d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.77-7.72 (m, 1H), 7.64 (dd, J = 0.8, 7.2 Hz, 1H), 7.59 (br dd, J = 2.8, 8.0 Hz, 1H), 7.40-7.26 (m, 5H), 4.49 (br d, J = 13.6 Hz, 2H), 4.08 (s, 2H), 3.64-3.58 (m, 2H), 3.21 (br s, 2H), 2.96-2.90 (m, 2H), 2.27-2.21 (m, 2H), 1.99 (br d, J = 10.8 Hz, 2H), 1.93-1.87 (m, 2H), 1.79 (br dd, J = 5.2, 11.2 Hz, 4H), 1.62-1.55 (m, 2H), 1.23 (br s, 1H); LCMS (ESI, M+1): m / z =654.3. EXAMPLE 363,4-difluorophenyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate EXAMPLE 373,4-difluorophenyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate

[0209] Step A. ethyl 3-oxopiperidine-4-carboxylate: To a solution of 1-(tert-butyl) 4-ethyl 3- oxopiperidine-1,4-dicarboxylate (40.0 g, 1.0 equiv) in MeOH (150 mL) was added HCl•MeOH (4 M, 250 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to afford the title compound. (40.0 g, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 172.3.

[0210] Step B. 1-benzyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate: To a mixture of ethyl 3- oxopiperidine-4-carboxylate (30.0 g, 1.0 equiv) and CbzCl (35.9 g, 1.2 equiv) in DCM (300 mL) were added TEA (88.7 g, 5.0 equiv) at 0 °C. The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, concentrated and purified with column chromatography [SiO2, petroleum ether / ethyl acetate=20 / 1 to 5 / 1] to afford the title compound (23.0 g, 43% yield) as colorless oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 12.09 (s, 1H), 7.39-7.32 (m, 5H), 5.16 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.12 (br s, 2H), 3.58 (t, J = 5.6 Hz, 2H), 2.36 (br s, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0211] Step C.1-benzyl 4-ethyl 3-hydroxypiperidine-1,4-dicarboxylate: To a solution of 1-benzyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (10.0 g, 1.0 equiv) in THF (100 mL) was added NaBH4 (1.95 g, 1.6 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was diluted with sat.NH4Cl (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organiclayers were washed with brine (100 mL ), dried over Na2SO4, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate=10 / 1 to 1 / 1] to afford the title compound (4.60 g, 46% yield) as yellow oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 7.40-7.28 (m, 5H), 5.14 (br s, 2H), 4.36-4.09 (m, 5H), 3.04 (br s, 1H), 2.97-2.84 (m, 1H), 2.56 (br d, J = 10.4 Hz, 1H), 2.21-2.01 (m, 1H), 1.87-1.70 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 308.3.

[0212] Step D. 1-benzyl 4-ethyl (3R,4R)-3-hydroxypiperidine-1,4-dicarboxylate and 1-benzyl 4- ethyl (3S,4S)-3-hydroxypiperidine-1,4-dicarboxylate: The residue was purified with SFC [column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 um); mobile phase: [CO2-EtOH(0.1%NH3H2O)]; B%:40%, isocratic elution mode] to afford the title compound (1.50 g, 33% yield) and (1.50 g, 33% yield).

[0213] Step E. ethyl (3R,4R)-3-hydroxypiperidine-4-carboxylate: To a solution of 1-benzyl 4-ethyl (3R,4R)-3-hydroxypiperidine-1,4-dicarboxylate (700 mg, 1.0 equiv) in ethyl acetate (8.00 mL) was added Pd / C (1.00 g, 10% purity) under N2atmosphere. The reaction was degassed and purged with H23 times. The reaction was stirred at 25 °C for 4 hours under H2 (50 psi). The mixture was filtered and concentrated to afford the title compound (300 mg, crude) as a yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 4.18 (q, J = 7.2 Hz, 2H), 4.07 (br s, 1H), 3.13-3.04 (m, 2H), 2.80- 2.66 (m, 3H), 2.59 (dt, J = 2.8, 12.4 Hz, 1H), 2.54-2.47 (m, 1H), 2.02-1.88 (m, 1H), 1.71 (br dd, J = 3.6, 13.2 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H).

[0214] Step F. ethyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate: To a mixture of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equiv) and K3PO4 (240 mg, 3.0 equiv) in DMF (3.00 mL) were added ethyl (3R,4R)-3-hydroxypiperidine-4-carboxylate (261 mg, 4.0 equiv) and 4Å molecular sieve (50.0 mg). The reaction was stirred at 60 °C for 2 hours. The mixture was filtered and purified by prep-HPLC [FA condition] to afford the title compound (180 mg, 80% yield) as yellow solid; LCMS (ESI, M+1): m / z = 604.3.

[0215] Step G. (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid: To a solution of ethyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate (90.0 mg, 1.0 equiv) in THF (1.50 mL) was added NaOH (2 M, 224 μL, 3.0 equiv). The reaction was stirred at 25 °C for 3 hours. The mixture was adjusted pH to 6. The mixture was washed with ethyl acetate (2 × 20.0 mL). The water layer was lyophilized to afford the title compound. (60.0 mg, crude) as an off white solid; LCMS (ESI, M+1): m / z = 576.3.

[0216] Step H. 3,4-difluorophenyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- hydroxypiperidine-4-carboxylate: To a solution of (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1- yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- hydroxypiperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 3,4-difluorophenol (33.9 mg, 3.0 equiv) in DCM (1.00 mL) were added DMAP (15.9 mg, 1.5 equiv) and EDCI (25.0 mg, 1.5 equiv). The reaction was stirred at 20 °C for 4 hours. The mixture was diluted with water (20.0 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20.0 mL ), dried over Na2SO4, concentrated and purified by prep-HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 um;mobile phase: [water(FA)-ACN];gradient:19%-49% B over 10 min] to afford the title compound (Example 36, 2.00 mg, 3.2% yield) as white solid;1H NMR (400 MHz, DMSO- d6) δ = 9.26 (d, J = 7.2 Hz, 1H), 8.30 (br d, J = 4.4 Hz, 1H), 8.18 (br d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.67-7.61 (m, 1H), 7.60-7.54 (m, 1H), 7.54-7.47 (m, 1H), 7.38-7.28 (m, 2H), 7.08-7.00 (m, 1H), 4.71-4.54 (m, 2H), 4.47 (br s, 1H), 4.09 (s, 2H), 3.74 (br dd, J = 4.8, 13.6 Hz, 2H), 3.29-3.17 (m, 3H), 3.02-2.91 (m, 2H), 2.56 (br d, J = 9.6 Hz, 2H), 2.30 (br d, J = 13.2 Hz, 1H), 1.91 (br dd, J = 6.0, 11.6 Hz, 3H), 1.82-1.75 (m, 3H), 1.63-1.56 (m, 2H); LCMS (ESI, M+1): m / z = 688.3.

[0217] Step I. ethyl (3S,4S)-3-hydroxypiperidine-4-carboxylate: To a solution of 1-benzyl 4-ethyl (3S,4S)-3-hydroxypiperidine-1,4-dicarboxylate (700 mg, 1.0 equiv) in EtOAc (8.00 mL) was added Pd / C (1.00 g) under N2atmosphere. The reaction was degassed and purged with H23 times. The reaction was stirred at 25 °C for 4 hours under H2 (50 psi). The mixture was filtered and concentrated to afford the title compound (300 mg, crude) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 4.15 (q, J = 7.2 Hz, 2H), 4.05 (br s, 1H), 3.06 (td, J = 3.2, 12.8 Hz, 2H),2.78 (br s, 2H), 2.67 (dd, J = 1.6, 13.2 Hz, 1H), 2.56 (dt, J = 2.8, 12.4 Hz, 1H), 2.51-2.41 (m, 1H), 1.92 (dq, J = 4.4, 12.8 Hz, 1H), 1.74-1.64 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H).

[0218] Step J. ethyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate: To a mixture of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250 mg, 1.0 equiv) and K3PO4 (300 mg, 3.0 equiv) in DMF (3.00 mL) were added ethyl (3S,4S)-3-hydroxypiperidine-4-carboxylate (245 mg, 3.0 equiv) and 4Å molecular sieve (50.0 mg). The reaction was stirred at 60 °C for 2 hours. The mixture was filtered and purified by prep-HPLC [FA condition] to afford the title compound (220 mg, 77% yield) as yellow solid; LCMS (ESI, M+1): m / z = 604.3.

[0219] Step K. (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid: To a solution of ethyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate (90.0 mg, 1.0 equiv) in THF (1.50 mL) was added NaOH (2 M, 224 μL, 3.0 equiv). The reaction was stirred at 25 °C for 3 hours. The mixture was adjusted pH to 6. The mixture was washed with ethyl acetate (2 × 20.0 mL). The water layer was lyophilized to afford the title compound (60.0 mg, crude) as an off white solid; LCMS (ESI, M+1): m / z = 576.3.

[0220] Step L.3,4-difluorophenyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4- carboxylate: To a mixture of (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 3,4-difluorophenol (33.9 mg, 3.0 equiv) in DCM (1.00 mL) were added DMAP (15.9 mg, 1.5 equiv) and EDCI (25.0 mg, 1.5 equiv).The reaction was stirred at 20 °C for 4 hours. The mixture was diluted with water (20.0 mL) and extracted with DCM (2 × 20 mL). The combined organic layer were washed with brine (20.0 mL ), dried over Na2SO4, concentrated and purified with prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [water(FA)-ACN];gradient:19%-49% B over 10 min] to afford the title compound (Example 37, 2.00 mg, 3.2% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.27 (d, J =7.2 Hz, 1H), 8.27 (br s, 1H), 8.19 (br d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.64 (dd, J = 7.6, 12.0 Hz, 1H), 7.61-7.56 (m, 1H), 7.55-7.48 (m, 1H), 7.39-7.29 (m, 2H), 7.09-7.00 (m, 1H), 4.73-4.55 (m, 2H), 4.48 (br s, 1H), 4.11 (s, 2H), 3.74 (br dd, J = 4.8, 13.2 Hz, 2H), 3.36-3.18 (m, 3H), 3.01-2.93 (m, 2H), 2.64-2.54 (m, 2H), 2.31 (br d, J = 13.2 Hz, 1H), 1.97- 1.87 (m, 3H), 1.81 (br dd, J = 6.0, 11.2 Hz, 3H), 1.65 - 1.56 (m, 2H); LCMS (ESI, M+1): m / z = 688.3.1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbaldehyde

[0221] Step A. (1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol: To a solution of 8-fluoro-7-(8- fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equiv) and piperidin-4-ylmethanol (65.1 mg, 3.0 equiv) in DMF (1.00 mL) were added 4Å molecular sieve (20.0 mg) and DIEA (73.1 mg, 3.0 equiv) .The reaction was stirred at 50 °C for 12 hours. The mixture was purified with prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [water (FA)-ACN]; gradient: 17%-47% B over 10 minutes] to afford the title compound (60.0 mg, 56% yield) as yellow solid; LCMS (ESI, M+1): m / z = 546.3.

[0222] Step B. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbaldehyde: To a solution of (1-(8-fluoro- 7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-4-yl)methanol (50.0 mg, 1.0 equiv) in DCM (1.00 mL) was added Dess- Martin reagent (77.7 mg, 2.0 equiv). The reaction was stirred at 20 °C for 2 hours. The mixture was quenched by Na2SO3(20.0 mL at 0 °C) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL ), dried over Na2SO4, concentrated and purified with prep-HPLC [column: Waters Xbridge 150 ×25 mm × 5um;mobile phase: [water (ammonia hydroxide v / v)-ACN];gradient:31%-61% B over 9 min] to afford the title compound (5.60 mg, 11% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 9.08 (s, 1H), 8.18 (br d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.78-7.70 (m, 1H), 7.66-7.55 (m, 2H), 7.31 (br dd, J = 7.2, 13.6 Hz, 1H), 4.64-4.50 (m, 1H), 4.40-4.34 (m, 1H), 4.05 (s, 2H), 3.62-3.54 (m, 1H), 2.96-2.89 (m, 2H), 2.85-2.73 (m, 1H), 2.56 (br s, 2H), 2.15-2.02 (m, 2H), 1.94-1.71 (m, 9H), 1.60-1.53 (m, 2H); LCMS (ESI, M+1): m / z = 544.3. EXAMPLE 39phenyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carboxylate

[0223] Step A. phenyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylate: To a mixture of 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (230 mg, 1.0 equiv) and phenol (65.0 mg, 2.0 equiv) in DCM (2.0 mL) were added DMAP (63.3 mg, 1.5 equiv) and EDCI (99.3 mg, 1.5 equiv). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (170 mg, 65.7% yield) as yellow solid; LCMS (ESI, M+1): m / z = 742.4.

[0224] Step B. phenyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carboxylate: To a solution of phenyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate (150 mg, 1.0 equiv) in MeCN (1.0 mL) was added HCl•dioxane (4 M, 39 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was concentrated. The residue was diluted with water (2.0 mL). The mixture was adjusted to pH = 7 with saturated NaHCO3 aqueous. The mixture was extracted with ethyl acetate (3 × 5.0 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified with prep- HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 25%-55% over 8 min] to afford the title compound (103 mg, 66% yield, 0.33 HCOOH) as white solid;1H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 10.12-9.77 (m, 1H), 9.12 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.51-7.39 (m, 2H), 7.38-7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.20-7.13 (m, 2H), 7.03 (d, J = 2.4 Hz, 1H), 5.42-5.20 (m, 1H), 4.60-4.43 (m, 2H), 4.19 (dd, J = 4.4, 10.4 Hz, 1H), 4.14-4.05 (m, 1H),3.70-3.53 (m, 2H), 3.20-3.04 (m, 4H), 2.93-2.80 (m, 1H), 2.41-2.31 (m, 1H), 2.23 (br d, J = 10.4 Hz, 2H), 2.19-2.07 (m, 3H), 2.06-1.92 (m, 3H), 1.91-1.75 (m, 3H), 0.73 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 698.3. EXAMPLE 403,4-difluorophenyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carboxylate

[0225] Step A. methyl 1-(2,7-dichloro-8-fluoropyrido d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (900 mg, 1.0 equiv) and DIEA (921 mg, 2.0 equiv) in DCM (18.0 mL) was added methyl piperidine-4-carboxylate (408 mg, 0.80 equiv) at -40 °C. The reaction was stirred at -40 °C for 0.5 hours. The mixture was diluted with water (30.0 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to afford the title compound (600 mg, 42% yield) as yellow solid; LCMS (ESI, M+1): m / z = 359.1.

[0226] Step B. methyl 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate:To a solution methyl 1- (2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equiv) in DMSO (0.5 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (665 mg, 3.0 equiv). The mixture was stirred at 100 °C for 3 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (600 mg, 88% yield) as yellow solid; LCMS (ESI, M+1): m / z = 482.2.

[0227] Step C. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylate: To a mixture of methyl 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4- carboxylate (500 mg, 1.0 equiv) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (561 mg, 1.5 equiv) in methoxycyclopentane (9.0 mL) and water (3.0 mL) were added [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphane methanesulfonate (75.5 mg, 0.10 equiv) and Cs2CO3(1.01 g, 3.0 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 90 °C for 5 hours. The mixture was filtered, concentrate and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (650 mg, 90% yield) as yellow solid; LCMS (ESI, M+1): m / z = 680.5.

[0228] Step D. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylic acid: To a mixture of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equiv) in water (1.5 mL) and THF (4.5 mL) was added NaOH (2 M in water, 4.0 equiv). The reaction was stirred at 25 °C for 2 hours. The mixture was adjusted to pH = 7 with HCl (2 M) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the title compound (480 mg, 96% yield) as yellow oil; LCMS (ESI, M+1): m / z = 666.3.

[0229] Step E.3,4-difluorophenyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate: To a mixture of 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equiv) and 3,4-difluorophenol (78.2 mg, 2.0 equiv) in DCM (2 mL) were added DMAP (55.1 mg, 1.5 equiv) and EDCI (86.4 mg, 1.5 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (200 mg, 81% yield) as yellow solid; LCMS (ESI, M+1): m / z = 778.4.

[0230] Step F. 3,4-difluorophenyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylate: To a mixture of 3,4-difluorophenyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (100 mg, 1.0 equiv) in MeCN (0.5 mL) was added HCl•dioxane (4 M, 31 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was concentrated. The residue was diluted with water (2.0 mL). The mixture was adjusted pH = 7 with saturated NaHCO3 aqueous solution and extracted with ethyl acetate (3 × 5.0 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified with prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 28%-58% over 10 min] to afford the title compound (42.6 mg, 41% yield, 0.28 HCOOH) as white solid;1H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 10.19-9.69 (m, 1H), 9.10 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.59-7.50 (m, 1H), 7.49-7.41 (m, 1H), 7.39-7.27 (m, 2H), 7.11-7.05 (m, 1H),7.03 (d, J = 2.4 Hz, 1H), 5.45-5.14 (m, 1H), 4.62-4.43 (m, 2H), 4.16 (dd, J = 4.0, 10.4 Hz, 1H), 4.10-4.02 (m, 1H), 3.69-3.54 (m, 2H), 3.16-2.99 (m, 4H), 2.87-2.76 (m, 1H), 2.43-2.30 (m, 1H), 2.26-2.17 (m, 2H), 2.17-2.08 (m, 2H), 2.08-1.92 (m, 4H), 1.90-1.72 (m, 3H), 0.80-0.65 (m, 3H); LCMS (ESI, M+1): m / z = 734.2. EXAMPLE 41methyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0231] Step A: methyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (50.1 mg, 1.0 equiv) and methyl piperidine-4-carboxylate (27.0 mg, 2.0 equiv) in DMF (1 mL) were added N-ethyl-N,N-diisopropylamine (73.2 mg, 6.0 equiv) and 4Å molecular sieve (10.0 mg). The reaction was stirred at 50 °C for 16 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, concentrated, and purified with prep-HPLC [Phenomenex luna C18 150 × 25 mm × 10um;A:water(FA), B: ACN, B%: 22%-52% over 7 mins] to afford the title compound (11.4 mg, 20% yield, 0.6 HCCOH) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.08 (s, 1H), 8.12 (br d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.76-7.66 (m, 1H), 7.65-7.58 (m, 1H), 7.54 (dt, J = 5.2, 8.0 Hz, 1H), 7.19 (dd, J = 7.6, 13.2 Hz, 1H), 4.62 (br d, J = 13.6 Hz, 2H), 4.52 (s, 2H), 3.79- 3.70 (m, 3H), 3.69-3.60 (m, 2H), 3.50-3.42 (m, 2H), 3.12-3.02 (m, 2H), 2.92-2.83 (m, 1H), 2.28- 2.02 (m, 8H), 2.02-1.90 (m, 4H); LCMS (ESI, M+1): m / z =574.5. EXAMPLE 424-(trifluoromethyl)phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0232] Step A. 4-(trifluoromethyl)phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To asolution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (45.0 mg, 1.0 equiv) and 4-(trifluoromethyl)phenol (39.1 mg, 3.0 equiv) in DCM (5 mL) were added 4-dimethylaminopyridine (19.7 mg, 2.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (30.8 mg, 2.0 equiv). The reaction was stirred at 40 °C for 16 hours. The mixture was concentrated and purified with prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 um, A: water (FA), B: ACN, B%: 35%- 65% over 7 mins] to afford the title compound (23.5 mg, 39 % yield, 0.1 HCOOH) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.18 (s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.79-7.72 (m, 1H), 7.67-7.56 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 7.2, 13.2 Hz, 1H), 4.64-4.46 (m, 4H), 3.64 (br t, J = 12.4 Hz, 2H), 3.51-3.40 (m, 2H), 3.24-3.10 (m, 3H), 2.26 (br d, J = 10.4 Hz, 2H), 2.15 (br dd, J = 6.0, 12.0 Hz, 2H), 2.09-1.91 (m, 8H); LCMS (ESI, M+1): m / z = 704.4. EXAMPLE 433,4-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0233] Step A. 3,4-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 3,4-difluorophenol (34.9 mg, 3.0 equiv) in DCM (3 mL) were added 4-dimethylaminopyridine (21.8 mg, 2.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (34.3 mg, 2.0 equiv). The reaction was stirred at 35 °C for 16 hours. The mixture was concentrated and purified by prep- HPLC [Phenomenex luna C18150 × 25 mm × 10 um; A: water (FA), B: ACN, B%: 32%-62% over 7 mins] to afford the title compound (21.5 mg, 33% yield) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 9.17 (s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.82-7.72 (m, 1H), 7.66-7.62 (m, 1H), 7.61-7.56 (m, 1H), 7.55-7.48 (m, 1H), 7.48-7.41 (m, 1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 7.12-7.04 (m, 1H), 4.62-4.41 (m, 4H), 3.69-3.57 (m, 2H), 3.38 (br s, 2H), 3.18- 3.04 (m, 3H), 2.23 (br d, J = 10.4 Hz, 2H), 2.13 (br dd, J = 6.4, 11.6 Hz, 2H), 2.08-1.88 (m, 8H); LCMS (ESI, M+1): m / z = 672.2. EXAMPLE 44phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate

[0234] Step A. phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 1-(8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido [4,3- d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and phenol (25.2 mg, 3.0 equiv) in DCM (5 mL) were added 4-dimethylaminopyridine (21.8 mg, 2.0 equiv) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (34.3 mg, 2.0 equiv). The reaction was stirred at 40 °C for 16 hours. The mixture was concentrated and purified with prep-HPLC [Phenomenex luna C18150 × 25mm × 10um;A: water (FA), B: ACN, B%: 30%-50% over 10 mins] to afford the title compound (2.07 mg, 3.6% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.21-8.17 (m, 1H), 7.98-7.89 (m, 1H), 7.81-7.70 (m, 1H), 7.68-7.56 (m, 2H), 7.50-7.39 (m, 2H), 7.36-7.25 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.60-4.44 (m, 2H), 4.28-4.15 (m, 2H), 3.66-3.57 (m, 2H), 3.15- 3.04 (m, 3H), 2.80-2.68 (m, 2H), 2.28-2.20 (m, 2H), 2.03-1.79 (m, 8H), 1.73-1.63 (m, 2H); LCMS (ESI, M+1): m / z = 636.5. EXAMPLE 45methyl (3R,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate

[0235] Step A. methyl 3-oxopiperidine-4-carboxylate: To a solution of 1-(tert-butyl) 4-methyl 3- oxopiperidine-1,4-dicarboxylate (2.00 g, 1.0 equiv) in ACN (20 mL) was added HCl•dioxane (4 M, 1.94 mL, 1.0 equiv). The reaction was stirred at 0°C for 1 hour. The mixture was concentrated to afford the title compound (1.20 g, crude) as white oil.

[0236] Step B. 1-benzyl 4-methyl 3-oxopiperidine-1,4-dicarboxylate: To a solution of methyl 3- oxopiperidine-4-carboxylate (1.20 g , 1.0 equiv) and benzyl carbonochloridate (1.56 g, 1.2 equiv) in THF (12 mL) was added TEA (1.08 g, 1.4 equiv) at 0 °C. The reaction was stirred at 25°C for 2 hours. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified with prep- HPLC (column: Phenomenex luna C18250 × 50mm × 10µm; A: water (FA), B: ACN, B%: 38%- 68% B over 21 min) to afford the title compound (1.27 g, 57% yield) as red oil; LCMS (ESI, M+1): m / z = 292.2.

[0237] Step C. 1-benzyl 4-methyl 3-hydroxypiperidine-1,4-dicarboxylate: To a solution of 1- benzyl 4-methyl 3-oxopiperidine-1,4-dicarboxylate (1.00 g, 1.0 equiv) in EtOH (10 mL) was added NaBH4 (64.9 mg, 0.5 equiv) at 0°C. The reaction was stirred at 0°C for 5 minutes. The mixture was quenched by saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by reversedphase flash [C18, 0.1% formic acid condition] to afford the title compound (500 mg, 44% yield) as colorless oil; LCMS (ESI, M+1): m / z = 293.9.

[0238] Step D. methyl 3-hydroxypiperidine-4-carboxylate: To a solution of 1-benzyl 4-methyl 3- hydroxypiperidine-1,4-dicarboxylate (500 mg, 1.0 equiv) in isopropanol (5 mL) was added Pd / C (100 mg, 10% purity). The reaction was degassed and purged with H23 times. The reaction was stirred at 25 °C for 1 hour under H2(15 psi). The mixture was filtered and concentrated to afford the title compound (270 mg, crude) as yellow oil.

[0239] Step E. methyl (3R,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate: To a solution of methyl 3-hydroxypiperidine-4-carboxylate (135 mg, 3.3 equiv) in DMF (1 mL) was added DIEA (164 mg, 5.0 equiv) and 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (135 mg, 1.0 equiv). The reaction was stirred at 40 °C for 12 hours. The mixture was filtered and purified by prep-HPLC [column: Phenomenex luna C18150 × 40mm × 15µm; A: water (FA), B: ACN, B%: 12%-42% B over 11 min] and SFC separation [column: ChiralPak IH, 250 × 50mm, 10µm; A: CO2, B: MeOH (0.1%NH3H2O), B%: 40%-40% B over 5.1 min] to afford the title compound (1.39 mg, 0.86% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.12 (s, 1H), 8.12 (br d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75-7.66 (m, 1H), 7.63-7.49 (m, 2H), 7.19 (dd, J = 7.6, 12.8 Hz, 1H), 4.63 (br d, J = 4.4 Hz, 1H), 4.55-4.49 (m, 1H), 4.41 (s, 2H), 4.15-4.06 (m, 1H), 3.75 (s, 3H), 3.69-3.58 (m, 1H), 3.50-3.34 (m, 2H), 2.96-2.84 (m, 2H), 2.74 (ddd, J = 4.4, 8.8, 10.8 Hz, 1H), 2.25-2.13 (m, 3H), 2.08-1.80 (m, 8H); LCMS (ESI, M+1): m / z = 590.5. EXAMPLE 46methyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate EXAMPLE 47methyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate

[0240] Step A. methyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate and methyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-cis-hydroxypiperidine-4-carboxylate: To a solution of methyl 3-hydroxypiperidine-4-carboxylate (135 mg, 3.3 equiv) in DMF (1 mL) were added DIEA (164 mg, 5.0 equiv) and 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (135 mg, 1.0 equiv). The reaction was stirred at 40 °C for 12 hours. The mixture was filtered and purified by prep-HPLC [column: Phenomenex luna C18150 × 25mm × 10µm; A: water (FA), B: ACN, B%: 18%-48% B over 9 min] and SFC separation [column: DAICEL CHIRALCEL OX, 250 × 30mm, 10µm; A: CO2, B: MeOH (0.1%NH3H2O), B%: 50%-50% B over 3.7 min] to afford two isomers.

[0241] methyl (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate (Example 46, 3.42 mg, 2.0% yield, HCOOH salt) as off-white solid; SFC : 94.4% ee. Column:Lux 3um Cellulose- 4 50 × 4.6mm I.D., 3 µm, mobile phase 40% (MeOH : ACN=4:1)(0.05%DEA), flow rate: 3 mL / min, detector: 220 nm, tR: 2.211 min;1H NMR (400 MHz, METHANOL-d4) δ = 9.24 (d, J = 11.2 Hz, 1H), 8.11 (br d, J = 8.0 Hz, 1H), 7.92-7.79 (m, 1H), 7.73-7.66 (m, 1H), 7.64-7.48 (m, 2H), 7.26-7.13 (m, 1H), 4.82 (br d, J = 2.4 Hz, 1H), 4.74 (br d, J = 13.6 Hz, 1H), 4.45 (br s, 1H), 4.41-4.35 (m, 2H), 3.76-3.66 (m, 4H), 3.28-3.21 (m, 2H), 2.98-2.80 (m, 3H), 2.44-2.28 (m, 1H), 2.20-2.10 (m, 2H), 2.07-1.76 (m, 8H); LCMS (ESI, M+1): m / z = 590.6;

[0242] methyl (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate (Example 47, 6.40 mg, 4.1% yield, HCOOH salt) as white solid; SFC : 94.4% ee. Column:Lux 3um Cellulose-4 50 × 4.6mm I.D., 3 µm, mobile phase 40% (MeOH : ACN=4:1)(0.05%DEA), flow rate: 3 mL / min, detector: 220 nm, tR: 2.719 min;1H NMR (400 MHz, METHANOL-d4) δ = 9.25 (d, J = 11.2 Hz, 1H), 8.11 (br d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.73-7.67 (m, 1H), 7.63-7.49 (m, 2H), 7.19 (dd, J = 7.6, 13.2 Hz, 1H), 4.83-4.78 (m, 1H), 4.74 (br d, J = 13.6 Hz, 1H), 4.49-4.36 (m, 3H), 3.77-3.65 (m, 4H), 3.29-3.25 (m, 1H), 2.98-2.85 (m, 3H), 2.44-2.28 (m, 1H), 2.23-2.12 (m, 2H), 2.11-1.93 (m, 6H), 1.92-1.82 (m, 3H); LCMS (ESI, M+1): m / z = 590.5. EXAMPLE 483,4-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylate

[0243] Step A: 1-benzyl 4-ethyl 5-hydroxyazepane-1,4-dicarboxylate. To a solution of 1-benzyl 4- ethyl 5-oxoazepane-1,4-dicarboxylate (11.0 g, 1.0 equiv) in THF (110 mL) was added NaBH4(1.39 g, 1.1 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was quenched with saturated NH4Cl solution (100 mL) at 0 °C and extracted with ethyl acetate (3 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, Petroleum ether / Ethyl acetate=3 / 1 to 1 / 1] to afford the title compound (5.00 g, 44% yield) as colorless oil;1H NMR (400 MHz, DMSO- d6) δ = 7.37-7.27 (m, 5H), 5.06 (s, 2H), 4.81-4.72 (m, 1H), 4.11-3.95 (m, 2H), 3.57-3.37 (m, 3H), 3.33-3.21 (m, 1H), 2.47-2.40 (m, 1H), 2.11-1.99 (m, 1H), 1.95-1.77 (m, 2H), 1.75-1.61 (m, 1H), 1.17 (dt, J = 2.4, 7.2 Hz, 3H).

[0244] Step B: 1-benzyl 4-ethyl 5-((methylsulfonyl)oxy)azepane-1,4-dicarboxylate. To a solution of 1-benzyl 4-ethyl 5-hydroxyazepane-1,4-dicarboxylate (7.00 g, 1.0 equiv) in DCM (70 mL) were added TEA (6.61 g, 9.1 mL, 3.0 equiv) and MsCl (6.47 g, 2.6 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was quenched with ice water (50 mL) slowly at 0 °C. The mixture was diluted with water (20 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (10.0 g, crude) as yellow oil;1H NMR (400 MHz, DMSO-d6) δ = 7.38-7.25 (m, 5H), 5.33-5.23 (m, 1H), 5.07 (s, 2H), 4.16-3.96 (m, 2H), 3.57-3.35 (m, 4H), 3.13 (d, J = 3.6 Hz, 2H), 3.10-3.05 (m, 1H), 2.92 (br d, J = 10.0 Hz, 1H), 2.32-2.22 (m, 1H), 2.10-1.90 (m, 3H), 1.20- 1.14 (m, 3H).

[0245] Step C: 1-benzyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate. To a solution of 1-benzyl 4-ethyl 5-((methylsulfonyl)oxy)azepane-1,4-dicarboxylate (9.00 g, 1.0 equiv) in THF (90 mL) was added DBU (6.86 g, 2.0 equiv). The reaction was stirred at 80 °C for 1 hour. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 3 / 1] to afford the title compound (4.00 g, 54% yield) as yellow oil;1H NMR (400 MHz, DMSO- d6) δ = 7.40-7.27 (m, 5H), 7.02 (br d, J = 1.6 Hz, 1H), 5.10 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.51 (br s, 4H), 2.64-2.58 (m, 2H), 2.44 (br d, J = 5.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H).

[0246] Step D: ethyl azepane-4-carboxylate. To a solution of 1-benzyl 4-ethyl 2,3,6,7-tetrahydro- 1H-azepine-1,4-dicarboxylate (3.00 g, 1.0 equiv) in THF (50 mL) was added Pd / C (700 mg, 10% purity). The reaction was degassed and purged with H23 times. The reaction was stirred at 40 °C for 6 hours under H2(50 Psi). The mixture was filtered and concentrated to afford the title compound (1.50 g, 88% yield) as yellow oil;1H NMR (400 MHz, DMSO-d6) δ = 4.03 (q, J = 7.2 Hz, 2H), 2.83-2.71 (m, 2H), 2.71-2.58 (m, 2H), 2.57-2.52 (m, 1H), 1.91-1.79 (m, 2H), 1.72-1.57 (m, 3H), 1.54-1.39 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H).

[0247] Step E: 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a mixture of 8-fluoro-7-(8-

[0248] fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 1.0 equiv) and 4Å molecular sieve (1.00 g) in DMF (20 mL) were added K3PO4(731 mg, 1.8 equiv) and ethyl azepane-4-carboxylate (1.61 g, 5.0 equiv). The reaction was stirred at 50 °C for 1 hour. The mixture was filtered, concentrated and purified by reversed phase flash [water (0.1% FA) / ACN] to afford the title compound (730 mg, 61% yield) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.17 (br d, J = 8.4 Hz, 1H), 7.97-7.91 (m, 1H), 7.77-7.70 (m, 1H), 7.66-7.53 (m, 2H), 7.35-7.26 (m, 1H), 4.19-4.08 (m, 2H), 4.06-4.03 (m, 3H), 3.95-3.83 (m, 2H), 2.99-2.87 (m, 2H), 2.68-2.60 (m, 1H), 2.57-2.52 (m, 2H), 2.29-2.17 (m, 1H), 2.07 (br d, J = 11.6 Hz, 2H), 1.98-1.84 (m, 5H), 1.83-1.65 (m, 5H), 1.56 (td, J = 7.2, 12.0 Hz, 2H), 1.16-1.12 (m, 3H).

[0249] Step F: 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylic acid. To a solution of ethyl 1-(8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carboxylate (390 mg, 1.0 equiv) in THF (4.0 mL) and MeOH (4.0 mL) was added NaOH solution (648 μL, 2.0 equiv, 2 M). The reaction was stirred at 25 °C for 1 hour. The mixture was quenched with HCl (3 M) and concentrated to afford the title compound (500 mg, HCl) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.53-8.50 (m, 1H), 8.54 (s, 1H), 8.17-7.76 (m, 1H), 7.66-7.55 (m, 2H), 7.30 (dd, J = 7.6, 12.8 Hz, 1H), 4.21-4.08 (m, 2H), 3.92-3.82 (m, 2H), 2.95-2.87 (m, 2H), 2.56-2.53 (m, 2H), 2.47-2.36 (m, 1H), 1.94 (br s, 5H), 1.88 (br dd, J = 5.6, 12.0 Hz, 3H), 1.83-1.69 (m, 5H), 1.60-1.52 (m, 3H).

[0250] Step G: 3,4-difluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylic acid (95.0 mg, 1.0 equiv) and 3,4- difluorophenol (64.6 mg, 3.0 equiv) in DCM (1.0 mL) were added DMAP (40.5 mg, 2.0 equiv) and EDCI (63.5 mg, 2.0 equiv). The reaction was stirred at 50 °C for 1 hour. The mixture was concentrated and purified by prep-HPLC [column: YMC-Actus Triart C18150 × 30 mm × 7 um; mobile phase: [water(FA)-ACN]; gradient:30%-60% B over 10 mins] and prep-HPLC [column: YMC-Actus Triart C18150 × 30 mm × 7 um; mobile phase: [water(FA)-ACN]; gradient:30%-60%B over 10 mins] to afford the title compound (19.5 mg, 17% yield, 0.2 HCOOH) as off-white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.21-9.16 (m, 1H), 8.18 (br d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.77-7.70 (m, 1H), 7.67-7.55 (m, 2H), 7.49 (br d, J = 9.2 Hz, 1H), 7.42-7.26 (m, 2H), 7.05-6.98 (m, 1H), 4.31-4.19 (m, 2H), 4.13-4.05 (m, 2H), 4.03-3.84 (m, 2H), 3.75-3.62 (m, 1H), 3.61-3.46 (m, 2H), 2.94 (br dd, J = 3.2, 5.6 Hz, 2H), 2.16-2.02 (m, 4H), 1.93-1.86 (m, 3H), 1.78- 1.65 (m, 4H), 1.63-1.54 (m, 3H); LCMS (ESI, M+1): m / z =686.4.methyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylate

[0251] Step A. methyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a (5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylate: To a solution of 1-(8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carboxylic acid (50.0 mg, 1.0 equiv) in dichloromethane (1 mL) were added oxalyl chloride (22.1 mg, 2.0 equiv) and dimethylformamide (6.37 mg, 1.0 equiv) at 0 °C. The reaction was stirred at 0 °C for 0.5 hour. The mixture was concentrated. To the residue was added methanol (27.9 mg, 10.0 equiv) dropwise at 0 °C. The reaction was stirred at 25 °C for 4hours. The mixture was filtered and the filtrate was purified by prep-HPLC [YMC-Actus Triart C18 150 * 30 mm * 7 um; mobile phase:[water(FA) - ACN]; B%: 23%-53% over 4 mins] to afford the title compound (5.79 mg, 11% yield, 0.3 HCOOH) as white solid;1H NMR (400 MHz, DMSO+D2O) δ = 9.12 (s, 1H), 8.15 (br d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.72 (br t, J = 8.0 Hz, 1H), 7.64-7.52 (m, 2H), 7.32-7.24 (m, 1H), 4.22-4.14 (m, 3H), 4.11-4.07 (m, 1H), 3.54 (br d, J = 6.0 Hz, 3H), 3.02 (br d, J = 4.4 Hz, 2H), 2.67-2.63 (m, 4H), 2.22-2.18 (m, 1H), 2.08- 2.04 (m, 2H), 2.01-1.87 (m, 4H), 1.86-1.81 (m, 2H), 1.80-1.72 (m, 3H), 1.67-1.59 (m, 3H); LCMS (ESI, M+1): m / z =588.54-(trifluoromethyl)phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylate

[0252] Step A. 4-(trifluoromethyl)phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylate: To a solution of 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylic acid (60.0 mg, 1.0 equiv) indichloromethane (1.0 mL) were added 4-(trifluoromethyl)phenol (50.9 mg, 3.0 equiv), 4- dimethylaminopyridine (25.6 mg, 2.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (40.1 mg, 2.0 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified by prep-HPLC [YMC-Actus Triart C18150 * 30 mm * 7 um; mobile phase: [water (FA)-ACN]; B%:33%-63% over 4 mins] to afford the title compound (34.9 mg, 46% yield, 0.6 HCOOH) as white solid;1H NMR (400 MHz, DMSO+D2O) δ = 9.18 (s, 1H), 8.16 (br d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.79-7.71(m, 3H), 7.62-7.54 (m, 2H), 7.32-7.24 (m, 3H), 4.33- 4.25(m, 3H), 4.14 (br s, 1H), 4.07-3.91 (m, 3H), 3.16 (br d, J = 4.8 Hz, 1H), 3.00-2.96 (m, 1H), 2.83-2.79 (m, 2H), 2.28-2.12 (m, 4H), 2.03-1.95 (m, 3H), 1.91 (br dd, J = 6.0, 12.0 Hz, 2H), 1.86- 1.78(m, 3H), 1.78-1.72 (m, 2H); LCMS (ESI, M+1): m / z =718.3.phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate

[0253] Step A. methyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate: To a solution of 8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (1 g, 1.0 equiv) in DMAC (10 mL) were added K3PO4(1.20 g, 3.0 equiv) and methyl piperidine-3-carboxylate (270 mg, 1.0 equiv). The reaction was stirred at 60 °C for 1 hour. The mixture was purified by reversed phase flash chromatography [C18,0.1 % formic acid condition] to afford the title compound (677 mg, 32% yield) as red solid; LCMS (ESI, M+1): m / z = 574.3.

[0254] Step B. 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid: To a solution of methyl 1- (8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (567 mg, 1.0 equiv) in EtOH (3 mL) and H2O (1 mL) was added LiOH•H2O (207 mg, 5.0 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (300 mg, 48% yield) as white solid; LCMS (ESI, M+1): m / z = 560.2.

[0255] Step C. phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate: To a solution of 1-(8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxylic acid (100 mg, 1.0 equiv) in DCM (1 mL) were added phenol (25.2 mg, 1.5 equiv), EDCI (51.4 mg, 1.5 equiv) and DMAP (32.8 mg, 1.5 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was purified by prep-HPLC [Phenomenex luna C18150 × 25 mm × 10µm; A: water (FA), B: ACN, B%: 30%- 60% over 7 min] to afford the title compound (20.9 mg, 33% yield, HCOOH salt) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.18 (d, J = 2.4 Hz, 1H), 8.19 (br d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.78-7.70 (m, 1H), 7.68-7.54 (m, 2H), 7.45-7.38 (m, 2H), 7.3-7.22 (m, 2H), 7.13- 7.06 (m, 2H), 4.62-4.49 (m, 1H), 4.27-4.15 (m, 1H), 4.15-4.06 (m, 2H), 4.03-3.91 (m, 1H), 3.80- 3.67 (m, 1H), 3.24-3.16 (m, 1H), 2.98-2.88 (m, 2H), 2.60-2.55 (m, 1H), 2.23 (br d, J = 7.2 Hz, 1H), 2.08-1.70 (m, 10H), 1.64-1.53 (m, 2H); LCMS (ESI, M+1): m / z = 636.4. EXAMPLE 522-fluorophenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate

[0256] Step A. phenyl 1-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate: To a solution of 1-(8- fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxylic acid (50 mg, 1.0 equiv) in DCM (0.5 mL) were added 2- fluorophenol (15.0 mg, 1.5 equiv), EDCI (25.7 mg, 1.5 equiv) and DMAP (16.4 mg, 1.5 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was purified by prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 30%- 60% over 7 min] to afford the title compound (20.9 mg, 33% yield, HCOOH salt) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.11 (d, J = 4.4 Hz, 1H), 8.01 (br d, J = 7.6 Hz, 1H), 7.82-7.71 (m, 1H), 7.68-7.58 (m, 2H), 7.46 (dt, J = 4.8, 8.0 Hz, 1H), 7.25-7.10 (m, 5H), 4.7-4.62 (m, 1H), 4.59-4.48 (m, 2H), 4.46-4.32 (m, 1H), 4.05-3.86 (m, 1H), 3.77-3.60 (m, 1H), 3.51 (br d, J = 4.0 Hz, 2H), 3.25-3.15 (m, 1H), 2.84-2.77 (m, 2H), 2.43-2.36 (m, 1H), 2.26 (br dd, J = 6.0, 12.8 Hz, 2H), 2.14-1.91 (m, 7H), 1.88-1.77 (m, 2H); LCMS (ESI, M+1): m / z = 654.4. EXAMPLE 53(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocan-4-yl)(3-methyl-1H- pyrazol-1-yl)methanone

[0257] Step A. azocane-4-carboxylic acid: A solution of 1-(tert-butoxycarbonyl)azocane- 4-carboxylic acid (300 mg, 1 equiv) in HCl•dioxane (2 M, 11.7 mL, 20 equiv) was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was diluted with methanol (2.0 mL) and neutralized with solid NaHCO3. The mixture was filtered and the filtrate was concentrated to afford the title compound (180 mg, 88% yield) as yellow oil;1H NMR (400 MHz, METHANOL-d4) δ 3.39-3.32 (m, 1H), 3.27-3.10 (m, 3H), 2.77-2.64 (m, 1H), 2.15- 2.06 (m, 2H), 1.99-1.85 (m, 4H), 1.80-1.67 (m, 2H).

[0258] Step B.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-4- carboxylic acid: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (280 mg, 1.0 equiv) and azocane-4-carboxylic acid (148 mg, 2.0 equiv) in DMF (2.5 mL) were added DIEA (244 mg, 4 equiv) and 4Å molecular sieve (20 mg). The reaction was stirred at 60 °C for 2 hours. Azocane-4-carboxylic acid (150 mg, 1.6 equiv, HCl salt) and DIEA (244 mg, 4.0 equiv) were added to the resulting mixture. Thereaction was stirred at 60 °C for 2 hours. The mixture was filtered and purified by reversed phase flash chromatography [water (0.1% FA) / acetonitrile] to afford the title compound (260 mg, 82% yield) as yellow solid; LCMS (ESI, M+1): m / z = 650.4.

[0259] Step C. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocan-4- yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-4-carboxylic acid (50 mg, 1 equiv) and EDCI (22.1 mg, 1.5 equiv) in DMF (0.5 mL) were added HOBt (12.5 mg, 1.2 equiv) and TEA (31.1 mg, 4.0 equiv). The reaction was stirred at 25 °C for 12 hours. The mixture was filtered and the filtrate was purified by prep-HPLC [Phenomenex Luna C18150 × 25 mm × 10 µm; A: water (NH4HCO3), B: ACN, B%: 56%-86% over 10 min] to afford the title compound (4.97 mg, 8.5% yield) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ 9.97-9.88 (m, 1H), 9.21- 9.16 (m, 1H), 8.25-8.19 (m, 1H), 7.81-7.71 (m, 1H), 7.38-7.29 (m, 2H), 6.98 (s, 1H), 6.44- 6.38 (m, 1H), 5.37-5.13 (m, 1H), 4.35-4.07 (m, 4H), 4.05-3.97 (m, 2H), 3.91-3.81 (m, 1H), 3.11-2.95 (m, 3H), 2.87-2.75 (m, 1H), 2.31-2.25 (m, 1H), 2.16-2.00 (m, 9H), 1.98-1.92 (m, 1H), 1.91-1.65 (m, 8H), 0.76-0.65 (m, 3H); LCMS (ESI, M+1): m / z = 714.5. EXAMPLE 54(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocan-5-yl)(3-methyl-1H- pyrazol-1-yl)methanone

[0260] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azocane-5-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (1 g, 1.0 equiv) and methyl azocane-5- carboxylate (309 mg, 1.0 equiv) in DMF (10 mL) were added DIEA (699 mg, 3.0 equiv) and PYBOP (1.41 g, 1.5 equiv). The reaction was stirred at 25 °C for 10 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography[C18, 0.1 % formic acid condition] to afford the title compound (700 mg, 52% yield) as yellow solid; LCMS (ESI, M+1): m / z = 708.4.

[0261] Step B. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azocane-5-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-5-carboxylate (650 mg, 1.0 equiv) in MeOH (2 mL) was added HCl•MeOH (4 M, 2.00 mL, 8.7 equiv). The reaction was stirred at 0 °C for 0.5 hours. The mixture was concentrated. The residue was diluted with water (5 mL), neutralized with solid NaHCO3 and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (600 mg, 86% yield) as yellow solid; LCMS (ESI, M+1): m / z = 664.4.

[0262] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-5- carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azocane-5-carboxylate (550 mg, 1.0 equiv) in MeOH (6 mL) were added LiOH•H2O (2 M, 1.81 mL, 4.4 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was purified by reversed phase flash chromatography[C18, 0.1 % formic acid condition] to afford the title compound (390 g, 72% yield) as white solid; LCMS (ESI, M+1): m / z = 650.4.

[0263] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocan-5- yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-5-carboxylic acid (60 mg, 1.0 equiv) and 3- methyl-1H-pyrazole (22.7 mg, 3.0 equiv) in DMF (0.5 mL) were added HATU (70.2 mg, 2.0 equiv) and DIEA (35.8 mg, 3.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was purified by reversed phase flash chromatography[C18, neutral condition] to afford the title compound (14.4 mg, 21% yield) as white solid;1H (400 MHz, CHLOROFORM-d) δ = 9.08 (d, J = 12.0 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 7.58-7.48 (m, 1H), 7.22-7.07 (m, 3H), 6.25 (d, J = 2.8 Hz, 1H), 5.39-5.17 (m, 1H), 4.23 (br d, J = 3.2 Hz, 4H), 4.02-3.78 (m, 3H), 3.38-3.09 (m, 3H), 3.04-2.93 (m, 1H), 2.61-2.50 (m, 1H), 2.27 (s, 4H), 2.24-2.04 (m, 10H), 2.02-1.83 (m, 4H), 0.85 (br t, J = 6.8 Hz, 3H); LCMS (ESI, M+1): m / z = 714.5.EXAMPLE 55(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocan-3-yl)(3-methyl-1H- pyrazol-1-yl)methanone

[0264] Step A. ethyl 3-(but-3-en-1-ylamino)propanoate: To a solution of ethyl 3- aminopropanoate hydrochloride (49.5 g, 1.5 equiv) in ACN (1000 mL) was added K2CO3(87.5 g, 3.0 equiv). The reaction was stirred at 25 °C for 1 hour.4-bromobut-1-ene (28.5 g, 1.0 equiv) was added. The reaction was stirred at 45 °C for 17 hours. The reaction was concentrated toafford the title compound (48.3 g, crude) as colorless oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 5.91-5.64 (m, 1H), 5.16-4.89 (m, 1H), 4.21-3.97 (m, 2H), 3.00-2.75 (m, 2H), 2.66 (t, J = 6.8 Hz, 1H), 2.56-2.34 (m, 2H), 2.29-2.09 (m, 1H), 1.34-1.14 (m, 3H).

[0265] Step B. ethyl 3-(but-3-en-1-yl(tert-butoxycarbonyl)amino)propanoate: To a solution of ethyl 3-(but-3-enylamino)propanoate (43.3 g, 1.0 equiv) in DCM (450 mL) was added TEA (51.1 g, 2.0 equiv) and Boc2O (82.7 g, 1.5 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate =1 / 0 to 20:1) to afford the title compound (40.2 g, 59% yield) as yellow oil.

[0266] Step C. ethyl 2-((but-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)pent-4-enoate: A solution of ethyl 3-(but-3-en-1-yl(tert-butoxycarbonyl)amino)propanoate (20.0 g, 1.0 equiv) in THF (200 mL) was degassed and purged with nitrogen 3 times. LDA (2 M, 1.5 equiv) was added slowly at -65 °C, the reaction was stirred at -40 °C for 1 hour.3-iodoprop-1-ene (13.6 g, 1.1 equiv) was added at -65 °C. The reaction was stirred at -40 °C for 0.5 hours. The mixture was quenched with water (100 mL) at 0 °C and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate =1 / 0 to 20:1) to afford the title compound (3.90 g, 15% yield) as yellow oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 5.81-5.64 (m, 2H), 5.11-4.95 (m, 4H), 4.16-4.06 (m, 2H), 3.50-3.21 (m, 3H), 3.17-3.05 (m, 1H), 2.95-2.68 (m, 1H), 2.39-2.11 (m, 4H), 1.44 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H).

[0267] Step D.1-(tert-butyl) 3-ethyl (Z)-3,4,7,8-tetrahydroazocine-1,3(2H)-dicarboxylate: To a solution of ethyl 2-((but-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)pent-4-enoate (1.00 g, 1.0 equiv) in DCM (150 mL) was added Grubbs catalyst (265 mg, 0.10 equiv). The reaction was purged with nitrogen 3 times. The reaction was stirred at 40 °C for 1.5 hours. The mixture was filtered, concentrated and purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate =1 / 0 to 20 / 1) to afford the title compound (650 mg, 71% yield) as brown oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 5.96-5.59 (m, 2H), 4.20-4.06 (m, 3H), 3.91- 3.75 (m, 1H), 3.42-3.05 (m, 1H), 3.01-2.89 (m, 1H), 2.83-2.58 (m, 1H), 2.49-2.21 (m, 3H), 2.19-2.06 (m, 1H), 1.47 (d, J = 3.2 Hz, 9H), 1.26 (td, J = 7.2, 10.3 Hz, 3H).

[0268] Step E.1-(tert-butyl) 3-ethyl azocane-1,3-dicarboxylate: To a mixture of Pd / C (200 mg, 10% purity) in EtOH (20 mL) was added 1-(tert-butyl) 3-ethyl (Z)-3,4,7,8- tetrahydroazocine-1,3(2H)-dicarboxylate (650 mg, 1.0 equiv). The suspension was degassed under vacuum and purged with H2 several times. The reaction was stirred under H2 (15 psi) at 25 °C for 1 hour. The mixture was filtered and concentrated to afford the title compound (381 mg, crude) as brown oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 4.20-4.05 (m, 2H), 3.94-3.60 (m, 2H), 3.16 (ddd, J = 6.8, 11.2, 14.4 Hz, 1H), 3.03-2.80 (m, 2H), 1.98-1.82 (m, 1H), 1.77-1.59 (m, 5H), 1.49-1.42 (m, 10H), 1.29-1.20 (m, 4H).

[0269] Step F. ethyl azocane-3-carboxylate: A solution of 1-(tert-butyl) 3-ethyl azocane- 1,3-dicarboxylate (381 mg, 1.0 equiv) in HCl•MeOH (2 M, 6.7 equiv) was stirred at 25 °C for 0.5 hours. The mixture was concentrated, diluted with MeOH (3 mL), adjusted pH to 8 with NaHCO3solid, filtered and concentrated to afford the title compound (236 mg, crude) as yellow oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 4.18-3.99 (m, 2H), 3.31-3.22 (m, 1H), 3.19-3.13 (m, 2H), 3.02-2.89 (m, 2H), 2.17-2.06 (m, 1H), 1.96-1.81 (m, 4H), 1.68 (br s, 3H), 1.20 (t, J = 7.2 Hz, 3H).

[0270] Step G. ethyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azocane-3-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (500 mg, 1.0 equiv), ethyl azocane-3- carboxylate (207 mg, 1.2 equiv) and DIEA (349 mg, 3.0 equiv) in DMF (5 mL) was added HATU (514 mg, 1.5 equiv). The reaction was stirred at 25 °C for 2 hours. The mixture was filtered, concentrated and purified by prep-HPLC [C18150 × 30 mm; A: water (FA), B: ACN, B%: 35%-65% over 7 min] to afford the title compound (120 mg, 12%, HCOOH) as white solid; LCMS (ESI, M+1): m / z = 722.4.

[0271] Step H. ethyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azocane-3-carboxylate: A solution of ethyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-3-carboxylate (170 mg, 1.0 equiv, FA) in HCl•MeOH (2 M, 45 equiv) was stirred at 25 °C for 1 hour. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH about 8 with NaHCO3solid, filtered and concentrated to afford the title compound (200 mg, crude) as yellow oil; LCMS (ESI, M+1): m / z = 678.4.

[0272] Step I. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-3- carboxylic acid: To a solution of ethyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azocane-3-carboxylate (180 mg, 1.0 equiv) in MeOH (5 mL) was added LiOH•H2O (2 M, 38 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was filtered, concentrated and purified by prep-HPLC [C18150 × 30 mm; A: water (FA), B: FA, B%: 25%-55% over 7 min] to afford the title compound (65.0 mg, 35%, HCOOH) as white solid.

[0273] Step J. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocan-3- yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azocane-3-carboxylic acid (30.0 mg, 1.0 equiv, HCOOH) and 3-methyl-1H-pyrazole (10.6 mg, 3.0 equiv) in DMF (1 mL) was added DIEA (22.3 mg, 4.0 equiv). The reaction was stirred at 25 °C for 10 minutes. HATU (32.8 mg, 2.0 equiv) was added. The reaction was stirred at 25 °C for 0.5 hours. The mixture was filtered and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN, B%: 58%-88% over 9 min] to afford the title compound (6.57 mg, 21%) as off-white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.17-8.93 (m, 1H), 8.17 (t, J = 3.2 Hz, 1H), 7.51 (td, J = 5.6, 9.2 Hz, 1H), 7.13 (br s, 3H), 6.32-6.23 (m, 1H), 5.36-5.12 (m, 1H), 4.85-4.62 (m, 1H), 4.59-4.31 (m, 2H), 4.09-3.99 (m, 1H), 3.96-3.72 (m, 1H), 3.70-3.52 (m, 1H), 3.30-2.99 (m, 3H), 2.97-2.87 (m, 1H), 2.64-2.37 (m, 2H), 2.34-2.22 (m, 4H), 2.19-2.07 (m, 3H), 2.04-1.98 (m, 2H), 1.97-1.73 (m, 9H), 0.86-0.79 (m, 3H); LCMS (ESI, M+1): m / z = 714.4.EXAMPLE 56(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(3-methyl- 1H-pyrazol-1-yl)methanone

[0274] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)pyrrolidine-3-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (1.00 g, 1.0 equiv), PyBOP (1.41 g, 1.5 equiv) in DMF (10 mL) were added DIEA (1.40 g, 6.0 equiv) and methyl pyrrolidine-3-carboxylate (448 mg, 1.5 equiv, HCl). The reaction was stirred at 40 °C for 12 hours. The mixture wasdiluted with H2O (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (1.20 g, 98% yield) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 9.30-9.22 (m, 1H), 7.93-7.85 (m, 1H), 7.69-7.64 (m, 1H), 7.46-7.39 (m, 1H), 7.27-7.10 (m, 4H), 5.39-5.19 (m, 3H), 4.24-3.89 (m, 6H), 3.69 (s, 3H), 3.45-3.41 (m, 4H), 3.14-3.08 (m, 2H), 3.07-3.06 (m, 1H), 2.89-2.79 (m, 1H), 2.44-2.31 (m, 2H), 2.29 (s, 2H), 2.19-2.11 (m, 2H), 2.09-1.98 (m, 2H), 1.91-1.75 (m, 4H); LCMS (ESI, M+1): m / z = 666.4.

[0275] Step B. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)pyrrolidine-3-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylate (1.10 g, 1.0 equiv) in MeOH (10 mL) was added HCl•MeOH (4 M, 24 equiv). The reaction was stirred at 25 °C for 12 hours. The mixture was concentrated, diluted with MeOH (10 mL), adjusted to pH about 8 with NaHCO3 solid, filtered and concentrated to afford the title compound (1.00 g, crude) as yellow solid.

[0276] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine- 3-carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)pyrrolidine-3-carboxylate (900 mg, 1.0 equiv) in MeOH (6 mL) and H2O (2 mL) was added LiOH•H2O (911 mg，15 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and adjust to pH=4 with HCl( 12 M), filtered to afford the title compound (800 mg, 88% yield, HCl) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 10.75-9.69 (m, 1H), 9.35-9.22 (m, 1H), 7.75 (dd, J = 6.0, 8.8 Hz, 1H), 7.39-7.29 (m, 2H), 7.10-7.02 (m, 1H), 5.50-5.29 (m, 1H), 4.40-4.25 (m, 2H), 4.06-3.91 (m, 2H), 3.55-3.21 (m, 4H), 3.16 (s, 1H), 3.04-2.96 (m, 3H), 2.36-2.09 (m, 6H), 1.97-1.86 (m, 2H), 1.73-1.69 (m, 2H), 0.80-0.66 (m, 3H); LCMS (ESI, M+1): m / z =608.3.

[0277] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)pyrrolidin-3-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (200 mg, 1.0 equiv), EDCI (94.7 mg, 1.5 equiv) in DCM (2 mL) were added DMAP (60.3 mg, 1.5 equiv) and 3-methyl-1H-pyrazole (50.1 mg, 2.0 equiv). The reaction was stirred at 25 °C for 12 hours. The mixture was filtered and purified by prep-HPLC [Waters Xbridge Prep OBD C18150 × 40mm × 10 µm; A: water (NH4HCO3), B: ACN, B%: 40%-70% over 20 min] to afford the title compound (42.3 mg, 18%) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.18- 9.02 (m, 1H), 8.21-8.10 (m, 1H), 7.48-7.41 (m, 1H), 7.15-7.08 (m, 1H), 7.07-7.02 (m, 1H), 6.99-6.83 (m, 1H), 6.33-6.27 (m, 1H), 5.39-5.15 (m, 1H), 4.41-4.17 (m, 5H), 4.11-3.87 (m, 2H), 3.42-3.24 (m, 2H), 3.23-3.12 (m, 1H), 2.99 (br d, J = 5.6 Hz, 1H), 2.50-2.38 (m, 2H), 2.34 (s, 3H), 2.33-2.17 (m, 3H), 2.16-2.09 (m, 2H), 2.00-1.88 (m, 3H), 0.83-0.74 (m, 3H); LCMS (ESI, M+1): m / z =672.4. EXAMPLE 57(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(4-methyl-1H- pyrazol-1-yl)methanone

[0278] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (10 g, 1.0 equiv) and methyl piperidine-4- carboxylate (7.7 g, 3.0 equiv) in DMF (30 mL) were added DIEA (7.0 g, 3.0 equiv) and PyBOP (14.1 g, 1.5 equiv). The reaction was stirred at 25 °C for 25 hours. The mixture was diluted with H2O (100 ml) and extracted with ethyl acetate (200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated to afford the title compound (10 g, 80% yield) as yellow solid; LCMS (ESI, M+1): m / z = 680.4.

[0279] Step B. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylate: A solution of methyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (10 g, 1 equiv) and HCl•MeOH (2 M, 30 mL, 4.08 equiv) was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was basified with saturated NaHCO3solution (25 mL) and extracted with ethyl acetate (2 × 50mL). The combined organic layers were washed with brine (2 × 2mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (5 g, 41% yield) as yellow solid; LCMS (ESI, M+1): m / z = 636.4.

[0280] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 4-carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate (5 g, 1.0 equiv) in MeOH (15 mL) was added LiOH•H2O (2 M, 15.7 mL, 4 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was purified by reversed phase flash chromatography[C18, 0.1 % formic acid condition] to afford the title compound (3 g, 57% yield) as white solid; LCMS (ESI, M+1): m / z = 622.4.

[0281] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 4-yl)(4-methyl-1H-pyrazol-1-yl)methanone

[0282] : To a solution of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylic acid (200 mg, 1.0 equiv), DIEA (208 mg, 5.0 equiv)， and HATU (147 mg, 1.2 equiv) in DMF (3.0 mL) was added 4-methyl-1H-pyrazole (79.2 mg, 3.0 equiv). The reaction was stirred at 30 °C for 2 hours. The mixture was filtered and purified by reversed phase flash [C18, H2O condition], followed by [column: Phenomenex Luna 150 × 25mm × 10µm; A: water (NH4HCO3), B: ACN; B%: 54%-84% over 10 min] to afford the title compound (11.0 mg, 4.8% yield) as a white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.09-9.05 (m, 1H), 8.09 (s, 1H), 7.71-7.64 (m, 2H), 7.33-7.21 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 5.46-5.22 (m, 1H), 4.79-4.66 (m, 2H), 4.41-4.25 (m, 2H), 4.14-4.03 (m, 1H), 3.773.61 (m, 2H), 3.28-3.17 (m, 2H), 3.11-3.00 (m, 1H), 2.58-2.45 (m, 1H), 2.40-2.18 (m, 5H), 2.13 (s, 4H), 2.11-2.01 (m, 4H), 2.00-1.86 (m, 2H), 0.81 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 686.4. EXAMPLE 58(3-(dimethylamino)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-4-yl)methanone

[0283] Step A. N,N-dimethyl-1H-pyrazol-3-amine: To a solution of 1H-pyrazol-3-amine (500 mg, 1.0 equiv) and formaldehyde (542 mg, 3.0 equiv) in MeOH (5 mL) were added AcOH (361 mg, 1.0 equiv).The reaction was stirred at 25 °C for 0.5 hours. NaBH3CN (227 mg, 0.6 equiv) was added to the mixture. The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was diluted with water (10 mL), neutralized with solid NaHCO3and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 0 / 1) to afford the title compound (150 mg, 19% yield) as colorless oil;

[0284] Step B. (3-(dimethylamino)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanone: To a solution of 1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (200 mg, 1.0 equiv) and N,N-dimethyl-1H-pyrazol-3-amine (53.6 mg, 1.5 equiv) in DMF (1 mL) were added HATU (245 mg, 2.0 equiv) and DIEA (125 mg, 3.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was purified by prep-HPLC [Waters Xbridge 150 × 25mm × 5µm; A: water (ammonia hydroxide v / v)-ACN; B: ACN, B%: 45%-75% over 10 min] to afford the title compound (36.8 mg, 15% yield) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.96 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 3.2 Hz, 1H), 7.57-7.49 (m, 1H), 7.21-7.12 (m, 2H), 7.07-6.96 (m, 1H), 6.03 (d, J = 3.2 Hz, 1H), 5.40-5.18 (m, 1H), 4.60 (br d, J = 12.4 Hz, 2H), 4.33-4.22 (m, 2H), 3.98-3.85 (m, 1H), 3.57-3.42 (m, 2H), 3.38-3.12 (m, 3H), 2.98 (s, 6H), 2.55-2.42 (m, 1H), 2.40-2.04 (m, 9H), 2.00-1.87 (m, 3H), 0.83 (br t, J = 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 715.4. EXAMPLE 59((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- azabicyclo[3.2.1]octan-8-yl)(1H-pyrazol-1-yl)methanone

[0285] Step A.3-benzyl 8-methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate: To a solution of (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid (1.15 g, 1.0 equiv) in DCM (10 mL) and MeOH (10 mL) was added TMSCHN2(2 M, 7.95 mL, 4.0 equiv) dropwise at 0 °C. The reaction was stirred at 20 °C for 3 hours. The mixture was quenched with CH3COOH (10 mL) at 0 °C. The mixture concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate=100 / 1 to 2 / 1] to afford the title compound (1.1 g, 44% yield, 96% purity) as colorless oil; LCMS (ESI, M+1): m / z = 304.2.

[0286] Step B.3-benzyl 8-methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate: 3-benzyl 8-methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (1.1 g, 1.0 equiv) was purified by SFC [column: DAICEL CHIRALPAK IK (250mm × 30mm,10um); mobile phase: CO2-i-PrOH; B%:30%, isocratic elution mode] to afford two peaks.

[0287] Peak 1: 3-benzyl 8-methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (652 mg, crude) as colorless oil; SFC: Column: Chiralpak IC-350 × 4.6mm I.D., 3umMobile phase: Phase A for CO2, and Phase B for IPA(0.05% DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40% Flow rate: 3mL / min; Detector: PDA; Column Temp: 35C;Back Pressure: 100Bar. tR: 1.533 min.

[0288] Peak 2: 3-benzyl 8-methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (400 mg, crude, RT = 1.773 min) as colorless oil; tR: 1.777 min.

[0289] Step C. methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylate: To a solution of 3-benzyl 8-methyl (1R,5S,8s)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (652 mg, 1.0 equiv) in MeOH (10 mL) was added Pd / C (100 mg, 10% purity) under N2 atmosphere. The reaction was degassed and purged with H2for 3 times. The reaction stirred at 20 °C for 2 hours under H2 (15 psi). The mixture was filtered through a pad of Celite and concentrated to afford the title compound (310 mg, crude) as colorless oil.

[0290] Step D. methyl (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate: To a solution of 5-ethyl-6-fluoro- 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (300 mg, 1.0 equiv) and methyl (1R,5S,8r)-3-azabicyclo[3.2.1]octane-8-carboxylate (128 mg, 1.5 equiv) in DMAc (1 mL) was added DIEA (261 mg, 4.0 equiv). The reaction was stirred at 80 °C for 2 hours. The mixture was purified by reversed phase flash [0.1% FA condition] to afford the title compound (275 mg, 61% yield) as off-white solid; LCMS (ESI, M+1): m / z = 662.3.

[0291] Step E. (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid: To a solution of methyl (1R,5S,8S)-3-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylate (255 mg, 1.0 equiv) in MeOH (1 mL) was added LiOH•H2O (2 M in H2O, 433 µL, 3.0 equiv). The mixture was stirred at 20 °C for 2 hours. The pH of the mixture was adjusted to 8 with 1N HCl at 0 °C. The mixture was purified by reversed phase flash [ 0.1% FA condition] to afford the title compound (180 mg, 70% yield) as off-white solid; LCMS (ESI, M+1): m / z = 648.4.

[0292] Step F. ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)(1H-pyrazol-1-yl)methanone: To a solution of (1R,5S,8S)- 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8- carboxylic acid (60 mg, 1.0 equiv) and 1H-pyrazole (50 mg, 8.0 equiv) in DMF (1 mL) were added TEA (75 mg, 8.0 equiv), HOBt (19 mg, 1.5 equiv) and EDCI (27 mg, 1.5 equiv). The reaction was stirred at 40 °C for 12 hours. The mixture was purified by prep- HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: water (NH4HCO3)-ACN; gradient:50%- 80% B over 53 minutes] to afford the title compound (9.1 mg, 13.6% yield) as white solid;1H NMR (400 MHz,CD3OD) δ = 9.11 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.08-7.03 (m, 1H), 6.56 (dd, J = 1.6, 2.8 Hz, 1H), 5.40-5.23 (m, 1H), 4.40-4.21 (m, 2H), 4.15-4.02 (m, 1H), 3.99-3.62 (m, 2H), 3.29-3.12 (m, 3H), 3.07-2.96 (m, 1H), 2.93-2.76 (m, 2H), 2.61-2.09 (m, 6H), 2.08-1.75 (m, 6H), 1.74-1.58 (m, 2H), 0.80 (dt, J = 2.0, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 698.4. EXAMPLE 60(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)(1H-pyrazol- 1-yl)methanone

[0293] Step A.2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine: To a solution of 7-chloro- 8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (100 g, 1.0 equiv) in toluene (300 mL) were added POCl3 (356 g, 5.0 equiv) and DIEA (132 g, 2.2 equiv) at -40 °C. The reaction was stirred at 110 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was quenched by addition saturated NaHCO3(2000 mL) at 0 °C. The mixture was filtered and the filter cake was dissolved in ethyl acetate (1000 mL). The organic phase was washed with saturated NaHCO3(1000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether (500 mL) at 25 °C for 30 min to afford the title compound (50 g, 81% yield) as yellow solid.

[0294] Step B.2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,2,2-trifluoroethanol (52 g, 1.1 equiv) in THF (200 mL) was added t-BuONa (2 M, 261 mL, 1.1 equiv) at 25 °C. The reaction was stirred at 25 °C for 1 hour. The mixture was added to a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (120 g, 1.0 equiv) in THF (1200 mL) at -40 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was quenched with H2O (500 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate, concentrated. The crude product was triturated with n-heptane (200 ml) and MTBE (20mL) at 25 °C for 60 min to afford the title compound (120 g, crude) as yellow solid; LCMS (ESI, M+1): m / z = 315.9.

[0295] Step C. 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,7-dichloro- 8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120 g, 1.0 equiv) and [(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (66.5 g, 1.1 equiv) in THF (1200 mL) was added Na2CO3 (121 g, 3.0 equiv). The reaction was stirred at 40 °C for 12 hours. The mixture was filtered and purified by reversed phase flash chromatography [water (FA, 0.1%) / acetonitrile] to afford the title compound (100 g, two steps: 57% yield) as yellow solid; LCMS (ESI, M+1): m / z = 439.1.

[0296] Step D. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)- 4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (28.4 g, 1.0 equiv), 5-ethyl-6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (25.6 g, 1.25 equiv) and Cs2CO3(1.5 M in H2O, 129 mL, 3.0 equiv) in methoxycyclopentane (300 mL) was added Ad2nBuP- Pd-G3 (7.07 g, 0.15 equiv). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 100 °C for 3 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [water (0.1% FA) / acetonitrile] to afford the title compound (16.8 g, 40% yield) as yellow solid; 1H NMR (400 MHz, chloroform-d) δ = 9.19 (d, J = 10.4 Hz, 1H), 7.54 (dd, J = 5.6, 8.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.16-7.11 (m, 1H), 6.96-6.84 (m, 1H), 5.46-5.22 (m, 1H), 5.05-4.71 (m, 2H), 4.56-4.32 (m, 2H), 3.48-3.21 (m, 3H), 3.13-3.01 (m, 1H), 2.47-2.32 (m, 4H), 2.32- 2.08 (m, 4H), 0.78 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 593.2.

[0297] Step E 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: To a solution of piperazine (727 mg, 5.0 equiv) in DMF (10 mL) was added 5-ethyl-6-fluoro-4-(8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (1.00 g, 1.0 equiv). The reaction was stirred at 25 °C for 2 hours. The mixture was purified by reversed phase flashchromatography [water (neutral) / acetonitrile = 1 / 1] to afford the title compound (914 mg, 90% yield) as yellow solid; LCMS (ESI, M+1): m / z = 579.4.

[0298] Step F. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin- 1-yl)(1H-pyrazol-1-yl)methanone: To a mixture of 1H-pyrazole (20.0 mg, 1.0 equiv), DIEA (151 mg, 4.0 equiv) in DCM (0.3 mL) was added bis(trichloromethyl) carbonate (120 mg, 1.4 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour. 5-ethyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(piperazin-1- yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (153 mg, 0.9 equiv) and DIEA (56.9 mg, 1.5 equiv) in DCM (0.7 mL) were added dropwise into the mixture at 0 °C. The reaction was stirred at 20 °C for 14 hours. The mixture was quenched with saturated NaHCO3 aqueous (5 mL) and extracted with DCM (4 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: water (ammonia hydroxide v / v) - acetonitrile; gradient: 42%-72% B over 10 minutes] to afford the title compound (75.7 mg, 38% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.95 (br s, 1H), 9.18 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.82 (s, 1H), 7.77 (dd, J = 6.0, 9.0 Hz, 1H), 7.40-7.30 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 6.53 (br d, J = 1.6 Hz, 1H), 5.39-5.17 (m, 1H), 4.24-3.97 (m, 10H), 3.12- 3.03 (m, 2H), 3.02-2.90 (m, 1H), 2.85-2.79 (m, 1H), 2.42-2.30 (m, 1H), 2.20-2.09 (m, 2H), 2.08-1.95 (m, 2H), 1.89-1.71 (m, 3H), 0.73 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 673.2. EXAMPLE 61(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methoxy- 1H-pyrazol-1-yl)methanone

[0299] StepA. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 4-yl)(3-methoxy-1H-pyrazol-1-yl)methanone; To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (350 mg, 1.0 equiv) and 3-methoxy-1H-pyrazole (55.2 mg, 1.0 equiv) in DMF (4 mL) were added HATU (428 mg, 2.0 equiv) and DIEA (364 mg, 5.0 equiv). The reaction was stirred at 25 °C for 3 hours. The mixture was diluted with water (4 mL) and extracted with ethyl acetate (4mL). The organic layer was dried over sodium sulfate, filtered and concentrated and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 54%-84% over 9 min] to afford the title compound (15.5 mg, 4 % yield) as yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.97 (s, 1H), 8.08 (d, J = 3.2 Hz, 1H), 7.60 - 7.51 (m, 1H), 7.23 - 7.16 (m, 2H), 7.06 - 6.97 (m, 1H), 6.02 (d, J = 2.8 Hz, 1H), 5.35 (br s, 1H), 4.69 - 4.55 (m, 2H), 4.29 (br d, J = 6.4 Hz, 2H), 3.99 (s, 3H), 3.90 (br dd, J = 5.2, 10.1 Hz, 1H), 3.59 - 3.43 (m, 2H), 3.36 - 3.14 (m, 3H), 3.05 (s, 1H), 2.56 - 2.40 (m, 2H), 2.27 - 2.06 (m, 7H), 1.99 - 1.87 (m, 3H), 0.83 (br t, J = 7.2 Hz, 3H) LCMS (ESI, M+1): m / z =702.4. EXAMPLE 621-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-N-(pyridin-2- yl)piperidine-4-carboxamide

[0300] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (2.00 g, 1.0 equiv) and methyl piperidine-4- carboxylate (1.03 g, 2.0 equiv) in DMF (20 mL) were added PyBOP (2.82 g, 1.5 equiv) andDIEA (1.40 g, 3.0 equiv). The reaction was stirred at 25 °C for 3 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (2.1 g, 74% yield) as yellow solid; LCMS (ESI, M+1): m / z = 680.3.

[0301] Step B. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (2.0 g, 1.0 equiv) in MeOH (6.2 mL) was added LiOH•H2O (2 M in H2O, 6.2 mL, 4.2 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (600 mg, 30% yield) as white solid; LCMS (ESI, M+1): m / z = 666.4.

[0302] Step C. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-N-methyl-N-(pyridin-2-yl)piperidine-4-carboxamide: To a solution of 1-(7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (300 mg, 1.0 equiv) and N-methylpyridin-2-amine (195 mg, 4.0 equiv) in THF (3 mL) were added 2-Chloro-1-Methylpyridinium Iodide (460 mg, 4.0 equiv) and DIEA (349 mg, 6.0 equiv). The reaction was stirred at 25 °C for 12 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (ammonia hydroxide), B: ACN, B%: 40%-70% over 10 min] to afford the title compound (112 mg, 32% yield) as yellow solid; LCMS (ESI, M+1): m / z = 756.4.

[0303] Step D.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-N-(pyridin-2-yl)piperidine-4-carboxamide: To a solution of 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-N-(pyridin-2-yl)piperidine-4- carboxamide (112 mg, 1.0 equiv) in MeOH (1 mL) was added HCl•MeOH (4 M, 1 mL, 27 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was concentrated, basified with saturated NaHCO3solution (6 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (FA), B: ACN, B%: 15%- 45% over 10 min] to afford the title compound (71.4 mg, 67% yield, 0.23 HCOOH) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.86 (s, 1H), 8.56-8.50 (m, 1H), 7.82 (br t, J = 7.8 Hz, 1H), 7.52-7.43 (m, 1H), 7.32-7.27 (m, 1H), 7.24 (s, 1H), 7.17-7.08 (m, 2H), 7.02-6.90 (m, 1H), 5.42-5.16 (m, 1H), 4.59-4.41 (m, 2H), 4.39-4.21 (m, 2H), 3.52 (br d, J = 14.0 Hz, 1H), 3.36 (s, 3H), 3.33 - 2.94 (m, 5H), 2.86-2.71 (m, 1H), 2.48-1.83 (m, 12H), 0.77 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 712.4. EXAMPLE 63 (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4-yl)(3-methyl-1H- pyrazol-1-yl)methanone

[0304] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carboxylate: To a mixture of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (400 mg, 1.0 equiv) and benzotriazol-1- yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate (751 mg, 2.0 equiv) in DMSO (4 mL) were added TEA (301 μL, 3.0 equiv) and methyl azepane-4-carboxylate (340 mg, 3.0 equiv). The reaction was stirred at 35 °C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (380 mg, 76% yield) as yellow oil; LCMS (ESI, M+1): m / z = 694.4.

[0305] Step B. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azepane-4-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylate (260 mg, 1.0 equiv) in ACN (2 mL) was added HCl•dioxane (4 M, 3.5 mL, 37 equiv) at 0 °C. The reaction was stirred at 15 °C for 1 hour. The mixture was adjusted to pH=7 with saturated NaHCO3(10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried overanhydrous sodium sulfate, concentrated to afford the title compound (300 mg, crude) as yellow oil.

[0306] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4- carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-4-carboxylate (300 mg, 1.0 equiv) in MeOH (3 mL) was added LiOH (2 M, 923 μL, 4.0 equiv). The reaction was stirred at 15 °C for 2 hours. The mixture was adjusted to pH=8 with HCl (1 M) and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (190 mg, 64% yield) as white solid; LCMS (ESI, M+1): m / z = 636.4.

[0307] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-4- yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-4-carboxylic acid (30.0 mg, 1.0 equiv) and 3-methyl-1H-pyrazole (7.75 mg, 2.0 equiv) in DMF (0.3 mL) were added HATU (35.9 mg, 2.0 equiv) and TEA (19.7 μL, 3.0 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [column: Waters xbridge 150 × 25 mm × 10 µm; A:water (NH4HCO3), B: ACN; B%: 53%-73% over 8 min] to afford the title compound (9.07 mg, 27% yield) as white solid;1H NMR (400 MHz, METHANOL-d4) δ = 9.18 (d, J = 2.4 Hz, 1H), 8.19 (t, J = 3.2 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.34-7.19 (m, 2H), 7.07 (dd, J = 2.4, 7.6 Hz, 1H), 6.37 (d, J = 1.2 Hz, 1H), 5.37-5.20 (m, 1H), 4.49-4.22 (m, 4H), 4.14 (br s, 1H), 4.02 (br d, J = 9.2 Hz, 1H), 3.88 (br s, 1H), 3.21 (br d, J = 19.8 Hz, 3H), 3.08-2.96 (m, 1H), 2.57-2.41 (m, 2H), 2.39-2.31 (m, 1H), 2.31-2.10 (m, 10H), 2.05-1.94 (m, 2H), 1.92- 1.77 (m, 2H), 0.87-0.77 (m, 3H); LCMS (ESI, M+1): m / z = 700.4. EXAMPLE 64(4-(dimethylamino)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidin-4-yl)methanone

[0308] Step A. tert-butyl 4-(dimethylamino)-1H-pyrazole-1-carboxylate: To a solution of tert-butyl 4-aminopyrazole-1-carboxylate (500 mg, 1.0 equiv) and formaldehyde (2.22 g, 37% purity, 10 equiv) in MeOH (10 mL) were added AcOH (164 mg, 1.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (514 mg, 3.0 equiv) was added to the reaction mixture. The reaction was stirred at 25 °C for 0.5 hours. The mixture was concentrated, basified with NaHCO3 (10 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 3 / 1) to afford the title compound (500 mg, 81% yield) as white oil; LCMS (ESI, M-99, M-55): m / z = 112.0,156.0

[0309] Step B. N,N-dimethyl-1H-pyrazol-3-amine: To a solution of tert-butyl 4- (dimethylamino)-1H-pyrazole-1-carboxylate (250 mg, 1 equiv) in DCM (0.5 mL) was added TFA (767 mg, 5.7 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was concentrated. The residue was basified by NaHCO3 (2 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound (130 mg, 99% yield) as colorless oil;

[0310] Step C. (3-(dimethylamino)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanone: To a solution of 1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (150 mg, 1.0 equiv) and N,N-dimethyl-1H-pyrazol-4-amine (53.6 mg, 2.0 equiv) in DMF (1 mL) were added HATU (183 mg, 2.0 equiv) and DIEA (93.5 mg, 3.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was purified by reversed phase flash chromatography [C18, water / ACN] to afford the title compound (10.3 mg, 5% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.94 (d, J = 7.2 Hz, 1H), 7.53-7.46 (m, 3H), 7.19-7.08 (m, 2H), 7.06-6.94 (m, 1H), 5.39-5.19 (m, 1H), 4.60 (br dd, J = 4.4, 8.4 Hz, 2H), 4.34-4.23 (m, 2H), 4.05-3.95 (m, 1H), 3.54-3.08 (m, 6H), 3.05-2.95 (m, 1H), 2.80 (s, 6H), 2.51-2.03 (m, 9H), 2.00-1.88 (m, 3H), 0.86-0.78 (m, 3H); LCMS (ESI, M+1): m / z = 715.3. EXAMPLE 65(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)(3-methyl-1H- pyrazol-1-yl)methanone

[0311] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (300 mg, 1.0 equiv), TEA (164 mg, 3.0 equiv) and benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate (422 mg, 1.5 equiv) in DMSO (3 mL) was added methyl piperidine-3-carboxylate (155 mg, 2.0 equiv). The reaction was stirred at 30 °C for 6 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (300 mg, 81% yield) as yellow oil; LCMS (ESI, M+1): m / z = 680.4.

[0312] Step B. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (150 mg, 1.0 equiv) in MeCN (0.5 mL) was added HCl•dioxane (4 M, 1.0 mL). The reaction was stirred at 0 °C for 0.5 hours. The mixture was adjusted to pH > 8 with saturated NaHCO3 aqueous (5 mL) at 0 ° C and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (120 mg, crude) as yellow solid; LCMS (ESI, M+1): m / z = 636.3.

[0313] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine- 3-carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-3-carboxylate (70.0 mg, 1.0 equiv) in THF (0.2 mL) and MeOH (0.3 mL) was added LiOH•H2O (13.9 mg, 3.0 equiv) in H2O (0.2 mL). The reaction was stirred at 20 °C for 1 hour. The mixture was adjusted to pH ≈ 6 with HCl (4 M, 0.8 mL) at 0 °C and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (50.0 mg, 72% yield) as white solid; LCMS (ESI, M+1): m / z = 622.3.

[0314] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 3-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a mixture of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid (80.0 mg, 1.0 equiv), EDCI (37.0 mg, 1.5 equiv), HOBt (26.1 mg, 1.5 equiv) and DIEA (49.9 mg, 3.0 equiv) in DMF (1.0 mL) was added 3-Methylpyrazole (21.1 mg, 2.0 equiv). The reaction was stirred at 20 °C for 12 hours.

[0315] The mixture was filtered and purified by reversed phase flash chromatography [C18, neutral condition] to afford the title compound (18.5 mg, 20% yield) as yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 9.94 (br d, J = 5.2 Hz, 1H), 9.30 (d, J = 5.6 Hz, 1H), 8.31-8.30 (m, 1H), 7.79-7.50 (m, 1H), 7.45-7.26 (m, 2H), 7.07-6.98 (m, 1H), 6.48-6.46 (m, 1H), 5.40-5.14(m, 1H), 4.73-4.68 (m, 1H), 4.45-4.42 (m, 1H), 4.17-4.09 (m, 1H), 4.07-4.03 (m, 1H), 3.76- 3.65 (m, 1H), 3.56-3.43 (m, 2H), 3.12-3.04 (m, 2H), 3.00 (br s, 1H), 2.85-2.78 (m, 1H), 2.33 (br s, 1H), 2.27 (d, J = 10.4 Hz, 3H), 2.21-2.10 (m, 3H), 2.05 (br s, 2H), 1.95 (br d, J = 8.8 Hz, 2H), 1.88-1.72 (m, 4H), 0.75-0.67 (m, 3H); LCMS (ESI, M+1): m / z = 686.4. EXAMPLE 66(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-vinyl-1H- pyrazol-1-yl)methanone

[0316] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 4-yl)(3-vinyl-1H-pyrazol-1-yl)methanone:

[0317] To a solution of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylic acid (300 mg, 1.0 equiv) and 3-vinyl-1H-pyrazole (300 mg, 6.6 equiv) in DMF (3 mL) were added HATU (367 mg, 2.0 equiv) and DIEA (312 mg, 5.0 equiv). The mixture was stirred at 25 °C for 0.5 hours. The mixture was filtered and purified by prep- HPLC [Waters Xbridge Prep OBD C18150 × 40 mm × 10 μm; A: water (NH4HCO3), B: ACN, B%: 45%-75% over 20 min] to afford the title compound (4.94 mg, 1.4% yield) as orange solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.98 (s, 1H), 8.20 (d, J = 3.0 Hz, 1H), 7.63 - 7.51 (m, 1H), 7.23-7.13 (m, 2H), 7.03 (dd, J = 2.4, 18.6 Hz, 1H), 6.77 (dd, J = 11.2, 17.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 5.91 (d, J = 17.8 Hz, 1H), 5.58 (d, J = 11.3 Hz, 1H), 5.41-5.19 (m, 1H), 4.70-4.58 (m, 2H), 4.36-4.21 (m, 2H), 4.09-3.96 (m, 1H), 3.61-3.42 (m, 2H), 3.37- 3.12 (m, 3H), 3.05-2.94 (m, 1H), 2.57-2.40 (m, 1H), 2.31 (br s, 1H), 2.28-2.06 (m, 7H), 2.02- 1.92 (m, 3H), 0.83 (br t, J = 7.4 Hz, 3H); LCMS (ESI, M+1): m / z = 698.4. EXAMPLE 67(1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4- yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0318] Step A. 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine: To a solution of POCl3 (187 g, 5.0 equiv) in toluene (150 mL) were added 7-chloro-8-fluoropyrido[4,3-d]pyrimidine- 2,4-diol (52.6 g, 1.0 equiv) and DIEA (69.4 g, 2.2 equiv). The reaction was stirred at 110 °C for 27 hours. The solvent was concentrated under vacuum. The mixture was poured into ice saturated NaHCO3solution (2.5 L) and maintained the pH was 8 then filtered. The filter cake was dissolved in ethyl acetate (1.5 L) and washed with saturated NaHCO3aqueous solution (1 L), saturated brine (1 L). The organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum to afford the title compound (50 g, 81% yield) as brown solid.

[0319] Step B.2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 2,2,2-trifluoroethanol (15.0 g, 0.9 equiv) in THF (150 mL) was added NaH (7.98 g, 60% purity, 1.2 equiv) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then the mixture was added to a solution of 2,4,7-trichloro-8- fluoropyrido[4,3-d]pyrimidine (42.0 g, 1.0 equiv) in THF (840 mL) at -40 °C. The reaction was stirred at -40 °C for 1 hour. The mixture was quenched with H2O (500 mL) and extracted with ethyl acetate (3 × 300 mL). The combinedorganic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 10 / 1 to 5 / 1] to afford the title compound (34.4 g, 53% yield) as yellow solid; LCMS [ESI, M+1]: 315.9.

[0320] Step C. 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 2,7-dichloro- 8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (33.3 g, 1.0 equiv), DIEA (54.5 g, 4.0 equiv) and 4Ǻ molecular sieve (4.0 g) in THF (340 mL) was added ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a- yl)methanol (20.1 g, 1.2 equiv). The reaction was stirred at 40 °C for 14 hours. The reaction mixture was diluted with H2O (20mL) and extracted with EtOAc (3 × 20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum and purified by reversed phase flash chromatography [water (FA, 0.1%) / acetonitrile] to afford the title compound (28.8 g, 62% yield) as yellow solid;1H NMR (400 MHz, chloroform-d) δ 8.98 (s, 1H), 5.40 - 5.19 (m, 1H), 5.02 (q, J = 8.0 Hz, 1H, 2H), 4.40 - 4.27 (m, 2H), 3.34 - 3.12 (m, 3H), 3.05 - 2.94 (m, 1H), 2.32 - 2.06 (m, 3H), 2.03 - 1.84 (m, 3H); LCMS [ESI, M+1]: 439.1.

[0321] Step D. 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a solution of 7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.20 g, 1.0 equiv) and 2-[2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl- triisopropyl-silane (3.85 g, 1.5 equiv) in methoxycyclopentane (25 mL) were added CataCxium (R) A Pd G3 (365 mg, 0.1 equiv) and Cs2CO3 (1.5 M in water, 2.5 equiv). The reaction was stirred at 100 °C for 3 hours under N2 atmosphere. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (2.80 g, 64% yield) as a brown solid. LCMS (ESI, M+1): m / z =789.4.

[0322] Step E. methyl 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.20 g, 1.0 equiv) and methyl piperidine-4- carboxylate (653 mg, 3.0 equiv) in DMF (12 mL) were added DIEA (590 mg, 3.0 equiv) and 4 Å molecular sieve (1.00 g) at 25 °C. The reaction was stirred at 70 °C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (800 mg, 56% yield) as a yellow solid. LCMS (ESI, M+1): m / z =832.5.

[0323] Step F. methyl 1-(8-fluoro-7-(7-fluoro-3-hydroxy-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of methyl 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (1.00 g, 1.0 equiv) in MeOH (10 mL) was added HCl / MeOH (2 M, 20 mL, 33.28 equiv) at 0 °C. The reaction was stirred at 0 °C for 0.5 hours. The mixture was concentrated under vacuum. The mixture was basified with NaHCO3(10 mL) and extracted with ethyl acetate (10 mL). The combined organic layers were dried over sodium sulfate and concentrated to afford the title compound (900 mg, crude) as yellow solid. LCMS (ESI, M+1): m / z =788.4.

[0324] Step G. methyl 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylate: To a solution of methyl 1-(8-fluoro-7-(7-fluoro-3-hydroxy-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (900 mg, 1.0 equiv) in DMF (9 mL) was added CsF (2.26 g, 13 equiv). The reaction was stirred at 40 °C for 14 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL).The organic layer was dried over sodium sulfate and concentrated to afford the title compound (900 mg, crude) as yellow solid. LCMS (ESI, M+1): m / z =632.3.

[0325] Step H. 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylic acid: To a solution of methyl 1-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equiv) in MeOH (5 mL) was added LiOH.H2O (1.5 M in water, 2.11 mL, 4.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was concentrated, diluted with water (5 mL) and extracted with ethyl acetate (7 mL). The organic layer was dried over sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (300 mg, 58% yield) as a yellow solid. LCMS (ESI, M+1): m / z =618.2.

[0326] Step I. (1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (150 mg, 242.87 μmol, 1 eq) and 3-methyl-1H-pyrazole (39.9 mg, 2.0 equiv) in DCM (0.5 mL) were added EDCI (69.8 mg, 1.5 equiv) and DMAP (44.5 mg, 1.5 equiv). The reaction was stirred at 25 °C for 12 hours. The mixture was concentrated, diluted with water (5 mL) and extracted with ethyl acetate (7 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by prep HPLC [Waters Xbridge Prep OBD C18150 × 40 mm × 10 µm; A: water (10mM NH4HCO3), B: ACN, B%: 38%-68% over 20 min] to afford the title compound (31.5 mg, 18 % yield) as orange solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.94 (d, J = 4.4 Hz, 1H), 8.15 (d, J = 2.8 Hz, 1H), 7.68 - 7.56 (m, 1H), 7.24 - 7.09 (m, 3H), 6.29 (d, J = 2.8 Hz, 1H), 5.40 - 5.13 (m, 1H), 4.64 (br d, J = 13.2 Hz, 2H), 4.31 - 4.19 (m, 2H), 4.07 - 3.97 (m, 1H), 3.52 (br t, J = 11.2 Hz, 2H), 3.33 - 3.10 (m, 3H), 3.04 - 2.90 (m, 1H), 2.80 (s, 1H), 2.35 (s, 3H), 2.33 - 2.27 (m, 1H), 2.21 (br d, J = 10.0 Hz, 3H), 2.11 (br d, J = 12.8 Hz, 3H), 2.03 - 1.90 (m, 3H); LCMS (ESI, M+1): m / z =682.4.EXAMPLE 68(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3-yl)(3-methyl-1H- pyrazol-1-yl)methanone

[0327] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-3-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (500 mg, 1.0 equiv) in DMSO (5 mL) wasadded TEA (456 mg, 5.0 equiv) and PyBOP (938 mg, 2.0 equiv). The reaction was stirred at 30 °C for 0.5 hours. Then methyl azepane-3-carboxylate (262 mg, 1.5 equiv, HCl) was added to the mixture. The reaction was stirred at 30 °C for 12 hours. The mixture was filtered and washed with DMSO (1 mL), and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (265 mg, 41% yield) as yellow solid; LCMS (ESI, M+1): m / z = 694.3.

[0328] Step B. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azepane-3-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3-carboxylate (143 mg, 1.0 equiv) in ACN (1 mL) was added HCl•dioxane (4 M, 2 mL, 39 equiv). The reaction was stirred at 20 °C for 0.5 hours. The mixture was adjusted pH to 8 with saturated NaHCO3aqueous solution (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to afford the title compound (160 mg, crude) as yellow solid; LCMS (ESI, M+1): m / z = 650.4.

[0329] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3- carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)azepane-3-carboxylate (160 mg, 1.0 equiv) in THF (0.6 mL), MeOH (0.4 mL) and H2O (0.6 mL) was added LiOH•H2O (31.0 mg, 3.0 equiv) at 0 °C. The reaction was stirred at 20 °C for 2 hours. The mixture was filtered and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (100 mg, 63% yield) as yellow solid; LCMS (ESI, M+1): m / z = 636.3.

[0330] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepan-3- yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3-carboxylic acid (100 mg, 1.0 equiv),DIEA (61.0 mg, 3.0 equiv), HOBt (31.9 mg, 1.5 equiv) and EDCI (45.2 mg, 1.5 equiv) in DMF (0.5 mL) was added 3-methyl-1H-pyrazole (25.8 mg, 2.0 equiv). The reaction was stirred at 20 °C for 12 hours. The mixture was filtered and purified by reversed phase flash [C18, H2O condition] to afford the title compound (17.6 mg, 15% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.93 (s, 1H), 9.26 (s, 1H), 8.34 (d, J = 2.7 Hz, 1H), 7.76 (dd, J = 6.0, 8.8 Hz, 1H), 7.43-7.28 (m, 2H), 7.01 (dd, J = 2.4, 14.0 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 5.30- 5.04 (m, 1H), 4.63-4.48 (m, 1H), 4.26-4.06 (m, 3H), 4.01-3.70 (m, 3H), 3.05-2.87 (m, 3H), 2.75 (br s, 1H), 2.40-2.31 (m, 1H), 2.26 (s, 3H), 2.20-2.13 (m, 1H), 2.12-2.01 (m, 3H), 1.97- 1.89 (m, 2H), 1.88-1.49 (m, 7H), 0.73 (td, J = 7.6, 17.2 Hz, 3H); LCMS (ESI, M+1): m / z = 700.3. EXAMPLE 69(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazepan-1-yl)(3- methyl-1H-pyrazol-1-yl)methanone

[0331] Step A. 4-(4-(1,4-diazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a solution of 1,4-diazepane (169 mg, 2.5 equiv) in DMF (3.5 mL) was added 5-ethyl-6- fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (400 mg, 1.0 equiv). The reaction was stirred at 25 °C for 2 hours. The mixture was purified by reversed phase flash [water (0.1% formic acid) / acetonitrile = 1 / 4] to afford the title compound (370 mg, 85.7% yield) as yellow solid; LCMS (ESI, M+1): m / z = 593.3.

[0332] Step B. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- diazepan-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 5-methyl-1H-pyrazole (30.0 mg, 1.0 equiv), DIEA (189 mg, 4.0 equiv) in DCM (0.5 mL) was added bis(trichloromethyl) carbonate (320 mg, 2.9 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 hour. 4-(4-(1,4-diazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (195 mg, 0.9 equiv) and DIEA (70.8 mg, 1.5 equiv) were added at 0 °C and the reaction was stirred at 20 °C for 14 hours. The mixture was quenched with saturated NaHCO3 aqueous (10 mL) and extracted with DCM (4 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash [water (0.1% formic acid) / acetonitrile = 1 / 1] and prep-HPLC [column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: (water (ammonia hydroxide v / v) – acetonitrile); gradient:46%- 76% B over 10 minutes] to afford the title compound (23.1 mg, 9% yield) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 9.90 (br s, 1H), 9.18 (s, 1H), 7.98 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.39-7.29 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.37-5.16 (m, 1H), 4.41-4.26 (m, 2H), 4.25-4.00 (m, 6H), 3.97-3.69 (m, 2H), 3.14-3.02 (m, 2H), 3.00 (s, 1H), 2.86-2.76 (m, 1H), 2.39-2.26 (m, 1H), 2.22-1.93 (m, 9H), 1.89-1.67 (m, 3H), 0.76- 0.64 (m, 3H); LCMS (ESI, M+1): m / z = 701.5. EXAMPLE 70(S,Z)-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0333] Step A. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidine-2,4-diol: To a mixture of 7-chloro-8-fluoro-pyrido[4,3- d]pyrimidine-2,4-diol (150 g, 1.0 equiv) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (263 g, 1.1 equiv) in dimethyl formamide (1500 mL) and water (300 mL) were added cataCXium® A Pd G3 (25.3 g, 0.05 equiv) and potassium phosphate (295 g, 2.0 equiv). The reaction was degassed and purged with nitrogen for 3 times and stirred at 100 °C for 12 hours under nitrogen atmosphere. The mixture was filtered and the filter cake was washed with dimethyl formamide (300 mL). The filtrate was concentrated, triturated with water (2000 mL), filtered and washed with water (1000 mL) andethanol (500 mL). The crude product was triturated with methyl tert-butyl ether (600 mL), filtered, and washed with methyl tert-butyl ether (200 mL) to afford 7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8- fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (102 g, 34.0% yield) as a yellow solid;1H NMR (400 MHz, DMSO-d6) δ = 12.29 - 11.37 (m, 2H), 8.84 (s, 1H), 7.90 (dd, J = 6.0, 8.8 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 5.34 (s, 2H), 3.42 (s, 3H), 2.42 - 2.29 (m, 1H), 2.25 - 2.12 (m, 1H), 0.79 (t, J = 7.2 Hz, 3H).

[0334] Step B. 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoropyrido[4,3-d]pyrimidine: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.80 g, 1.0 equiv) in toluene (30.0 mL) was added dropwise POCl3 (3.34 g, 5.0 equiv) and DIEA (2.28 mL, 3.0 equiv) at 0 °C. The reaction was stirred at 100 °C for 1 hour. The mixture was concentrated then poured into saturated NaHCO3solution (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 20 / 1 to 5 / 1) to afford the title compound (1.60 g, 81% yeild) as yellow oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.54 (s, 1H), 7.73 (dd, J = 6.0, 9.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.30 (t, J = 9.2 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 5.31 (d, J = 2.0 Hz, 2H), 3.53 (s, 3H), 2.48- 2.35 (m, 1H), 2.21-2.07 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H).

[0335] Step C. methyl 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of 2,4- dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidine (610 mg, 1.0 equiv) in DCM (12 mL) was added TEA (411 mg, 3 equiv) at -40 °C. A solution of methyl piperidine-4-carboxylate (155 mg, 0.8 equiv) in DCM (3 mL) was added dropwise to the mixture at -40 °C. The reaction was stirred at -40 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with dichloromethane (2 × 20 mL). The organic layers were dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate 20 / 1 to 2 / 1) to afford the title compound (940 mg, 56% yield) as yellow solid;1H NMR (400 MHz, METHANOL-d4) δ 9.18 (s, 1H), 7.84-7.76 (m, 1H), 7.63 (d, J = 2.8 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H),5.33 (s, 2H), 4.68-4.59 (m, 2H), 3.73 (s, 3H), 3.72-3.63 (m, 2H), 3.50 (s, 3H), 2.93-2.83 (m, 1H), 2.54-2.40 (m, 1H), 2.27-2.13 (m, 3H), 2.02-1.89 (m, 2H), 0.81 (t, J = 7.6 Hz, 3H).

[0336] Step D. methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)piperidine-4-carboxylate: To a solution of (S,Z)-(2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (169 mg, 1.1 equiv) in THF (10 mL) was added NaH (89.8 mg, 60% purity, 2.5 equiv) at 0 °C. The reaction was stirred at 0 °C for 10 minutes. Methyl 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen- 1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (500 mg, 1 equiv) was added into the mixture. The reaction was stirred at 0-20 °C for 1 hour. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (300 mg, 43% yield) as yellow solid; LCMS (ESI, M+1): m / z = 692.4.

[0337] Step E. methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- ((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)piperidine-4-carboxylate: To a mixture of methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (350 mg, 1 equiv) in ACN (1.25 mL) was added HCl•dioxane (2 M, 5.06 mL, 20 equiv) dropwise. The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was basified with saturated NaHCO3 solution (6 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (300 mg, 82% yield) as yellow solid; LCMS (ESI, M+1): m / z = 648.4.

[0338] Step F. (S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidine-4-carboxylic acid: To a solution of methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (300 mg, 1.0 equiv) in EtOH (4.5 mL) was added a solution of NaOH (92.6 mg, 5 equiv) in H2O (1.5 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and purified by reversed phase flash chromatography [water (NH3•H2O) / acetonitrile] to afford the title compound (200 mg, 67% yield) as yellow solid; LCMS (ESI, M+1): m / z = 634.3.

[0339] Step G. (S,Z)-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of (S,Z)-1-(7-(8-ethyl- 7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 1 equiv) and EDCI (45.4 mg, 1.5 equiv) in DMF (1 mL) were added HOBt (25.6 mg, 1.2 equiv) and TEA (63.9 mg, 4.0 equiv) followed by 3-methyl-1H-pyrazole (38.9 mg, 3.0 equiv). The reaction was stirred at 25 °C for 12 hours. The mixture was filtered and purified by prep- HPLC [Phenomenex Luna C18150 × 25 mm × 10 µm; A: water (NH4HCO3), B: ACN, B%: 56%-86% over 10 min], followed by prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 20%-50% over 1 min]. The desired fractions were diluted with water (60 mL) and extracted with dichloromethane (2 × 20 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (2.50 mg, 2.2% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d3) δ 9.03-8.96 (m, 1H), 8.19-8.14 (m, 1H), 7.61-7.54 (m, 1H), 7.25-7.19 (m, 2H), 7.08-7.02 (m, 1H), 6.65-6.37 (m, 1H), 6.33-6.28 (m, 1H), 4.72-4.61 (m, 2H), 4.36-4.19 (m, 2H), 4.09-3.99 (m, 1H), 3.98-3.85 (m, 1H), 3.61-3.49 (m, 2H), 3.48-3.40 (m, 1H), 3.30-3.15 (m, 1H), 2.82-2.72 (m, 1H), 2.72- 2.62 (m, 1H), 2.56-2.45 (m, 1H), 2.40-2.32 (m, 4H), 2.28-2.06 (m, 7H), 1.98-1.91 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 698.5. EXAMPLE 71((3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0340] Step A. (3S,4R)-3-methylpiperidine-4-carboxylic acid: To a solution of (3S,4R)-1- (tert-butoxycarbonyl)-3-methylpiperidine-4-carboxylic acid (250 mg, 1.0 equiv) in ACN (0.5 mL) were added HCl•dioxane (2 M, 0.5ml, 1.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was concentrated to afford the title compound (120 mg, 73% yield) as white solid; MS (ESI, M+1): m / z = 144.4

[0341] Step B. (3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-methylpiperidine-4-carboxylic acid: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (130 mg, 1.0 equiv) in DMF (1.5 mL) were added (3S,4R)-3-methylpiperidine-4-carboxylic acid (62.8 mg, 2.0 equiv) and K3PO4 (279 mg, 6.0 equiv). The reaction was stirred at 60 °C for 0.5 hours. The mixture was purified by prep-HPLC [Phenomenex luna C18150 × 25mm × 10µm; A: water(FA)-ACN;B:CAN, B%: 15%-45% over 9 min] to afford the title compound (35 mg, 24% yield) as white solid; LCMS (ESI, M+1): m / z = 636.4.

[0342] Step C. ((3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of (3S,4R)- 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-4- carboxylic acid (30 mg, 1.0 equiv) and 3-methyl-1H-pyrazole (11.6 mg, 3.0 equiv) in DMF (0.5 mL) were added HATU (35.9 mg, 2.0 equiv) and DIEA (18.3 mg, 3.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was purified by reversed phase flash chromatography [C18, water / ACN] to afford the title compound (18.0 mg, 54% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.97 (d, J = 5.6 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.62-7.52 (m, 1H), 7.25-7.17 (m, 2H), 7.05 (dd, J = 2.8, 6.4 Hz, 1H), 6.33 (d, J = 2.8 Hz, 1H), 5.40-5.21 (m, 1H), 4.77-4.69 (m, 1H), 4.64-4.55 (m, 1H), 4.29 (d, J = 3.6 Hz, 2H), 3.84 (tt, J = 3.6, 11.2 Hz, 1H), 3.43-3.34 (m, 1H), 3.33-3.16 (m, 3H), 3.15-3.04 (m, 1H), 3.04- 2.96 (m, 1H), 2.55-2.36 (m, 5H), 2.36-2.29 (m, 1H), 2.27-2.18 (m, 3H), 2.17-2.11 (m, 1H), 2.01-1.90 (m, 4H), 1.01 (t, J = 7.2 Hz, 3H), 0.88-0.80 (m, 3H); LCMS (ESI, M+1): m / z = 700.4. EXAMPLE 72(4-(tert-butyl)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)piperidin-4-yl)methanone

[0343] Step A. (4-(tert-butyl)-3H-2l4-pyrazol-2-yl)(1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanone: To a solution of 1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50.0 mg, 1.0 equiv) and 4-tert-butyl-1H-pyrazole (20.0 mg, 2.0 equiv) in DMF (1 mL) was added EDCI (23.1 mg, 1.5 equiv), HOBt (5.43 mg, 0.5 equiv) and TEA (24.4 mg, 3.0 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL). The combined organic layer was dried over sodium sulfate, concentrated and purified by prep-HPLC [Waters Xbridge C18150 × 25 mm × 5 µm; A: water (10mM NH4HCO3), B: ACN, B%: 62%-92% over 9min] to afford the title compound (11.8 mg, 19 % yield) as white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.93 (s, 1H), 9.10 (s, 1H), 8.16 (d, J = 0.4 Hz, 1H), 7.97 (d, J = 0.4 Hz, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 5.41 - 5.14 (m, 1H), 4.63 - 4.52 (m, 2H), 4.20 - 4.11 (m, 1H), 4.09 - 3.95 (m, 2H), 3.67 - 3.50 (m, 2H), 3.16 - 2.98 (m, 4H), 2.87 - 2.77 (m, 1H), 2.14 (br d, J = 10.0 Hz, 4H), 2.08 - 1.97 (m, 3H), 1.97 - 1.88 (m, 2H), 1.86 - 1.75 (m, 3H), 1.26 (s, 9H), 0.72 (t, J = 7.2 Hz, 3H) LCMS (ESI, M+1): m / z = 728.5. EXAMPLE 73(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3,4,5- trimethyl-1H-pyrazol-1-yl)methanone

[0344] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 4-yl)(3,4,5-trimethyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (50 mg, 1.0 equiv) and 3,4,5-trimethyl-1H-pyrazole (26.6 mg, 3.0 equiv) in DMF (1 mL) were added HATU (61.2 mg, 2.0 equiv) and DIEA (31.2 mg, 3.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was purified by prep-HPLC[Waters Xbridge 150 × 25mm × 5µm;mobile phase: [water( NH4HCO3)-ACN];gradient:50%-80% B over 15 min] to afford the title compound(6.31 mg, 11% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.99 (s, 1H), 7.61-7.53 (m, 1H), 7.25-7.18 (m, 2H), 7.06 (dd, J = 2.8, 16.8 Hz, 1H), 5.41-5.20 (m, 1H), 4.65 (br d, J = 13.2 Hz, 2H), 4.34-4.21 (m, 2H), 4.15-4.05 (m, 1H), 3.60-3.44 (m, 2H), 3.33- 3.13 (m, 3H), 3.05-2.95 (m, 1H), 2.49 (s, 4H), 2.31 (br d, J = 6.0 Hz, 1H), 2.24 (s, 4H), 2.21- 2.12 (m, 3H), 2.11-2.02 (m, 3H), 2.01-1.92 (m, 6H), 0.84 (t, J = 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 714.4. EXAMPLE 74(3,5-dimethyl-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)piperidin-4-yl)methanone

[0345] Step D. (3,5-dimethyl-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanone: To a solution of 1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equiv) and 3,5-dimethyl-1H-pyrazole (46.4 mg, 3.0 equiv) in DMF (1 mL) were added HATU (122 mg, 2.0 equiv) and DIEA (62.4 mg, 3.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was purified by reversed phase flash chromatography[C18,neutral condition] to afford the title compound (28.3 mg, 24% yield) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.99 (s, 1H), 7.64-7.51 (m, 1H), 7.25-7.18 (m, 2H), 7.10-7.00 (m, 1H), 6.02 (s, 1H), 5.41-5.20 (m, 1H), 4.71-4.61 (m, 2H), 4.34-4.21 (m, 2H), 4.17-4.03 (m, 1H), 3.59-3.46 (m, 2H), 3.35-3.14 (m, 3H), 3.06-2.95 (m, 1H), 2.57 (s, 3H), 2.54-2.44 (m, 1H), 2.33-2.27 (m, 4H), 2.26-2.12 (m, 5H), 2.11-2.04 (m, 2H), 2.01-1.87 (m, 3H), 0.84 (t, J = 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 700.4. EXAMPLE 75(3-(tert-butyl)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)piperidin-4-yl)methanone

[0346] Step A. (3-(tert-butyl)-1H-pyrazol-1-yl)(1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanone: To a solution of 1-(7-(8- ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equiv) and 3-tert-butyl-1H-pyrazole (59.9 mg, 3.0 equiv) in DMF (1 mL) were added HATU (91.7 mg, 1.5 equiv) and DIEA (62.4 mg, 3.0 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and purified by prep-HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 54%-84% over 15 min]. The aqueous was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (27.0 mg, 23% yield) as yellow solid;1H NMR (400 MHz, chloroform-d) δ = 8.99 (s, 1H), 8.15 (d, J = 2.8 Hz, 1H), 7.57 (dd, J = 5.6, 9.2 Hz, 1H), 7.24 - 7.17 (m, 2H), 7.08 - 7.00 (m, 1H), 6.39 (d, J = 2.8 Hz, 1H), 5.41 - 5.20 (m, 1H), 4.70 - 4.57 (m, 2H), 4.34 - 4.22 (m, 2H), 4.09 - 3.98 (m, 1H), 3.62 - 3.46 (m, 2H), 3.42 - 3.10 (m, 3H), 3.06 - 2.94 (m, 1H), 2.56 - 2.43 (m, 1H), 2.38 - 2.29 (m, 1H), 2.28 - 2.20 (m, 3H), 2.20 - 2.07 (m, 4H), 2.02 - 1.90 (m, 3H), 1.35 (s, 9H), 0.83 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 728.4. EXAMPLE 76(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-isopropyl- 1H-pyrazol-1-yl)methanone

[0347] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 4-yl)(3-isopropyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 1.0 equiv) and 3-isopropyl-1H-pyrazole (53.2 mg, 3.0 equiv) in DMF (1 mL) were added HATU (91.7 mg, 1.5 equiv) and DIEA (62.4 mg, 3.0 equiv). The reaction was stirred at 25 °C for 2 hours. The mixture was filtered and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 50%-80% over 15 min] to afford the title compound (13.9 mg, 12% yield) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.97 (s, 1H),8.16 (d, J = 2.8 Hz, 1H), 7.58-7.51 (m, 1H), 7.22-7.14 (m, 2H), 7.07-6.96 (m, 1H), 6.34 (d, J = 2.8 Hz, 1H), 5.41-5.18 (m, 1H), 4.70-4.55 (m, 2H), 4.36-4.24 (m, 2H), 4.10-3.95 (m, 1H), 3.60-3.45 (m, 2H), 3.40-3.11 (m, 3H), 3.09-2.94 (m, 2H), 2.55-2.43 (m, 1H), 2.38-2.28 (m, 1H), 2.27-2.17 (m, 4H), 2.17-2.08 (m, 3H), 2.00-1.90 (m, 3H), 1.31 (d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 714.3. EXAMPLE 77(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)(3- methyl-1H-pyrazol-1-yl)methanone

[0348] Step A. methyl 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (100 mg, 1.0 equiv) in DMF (2 mL) were added DIEA (70.0 mg, 3.0 equiv) and PyBOP (141 mg, 1.5 equiv) slowly at 25 °C, the reaction was stirred at 25 °C for 20 minutes. And then methyl 1,4-oxazepane-6-carboxylate (34.4 mg, 1.2 equiv) was added at 25 °C slowly. The reaction was stirred at 25 °C for 2 hours. The mixture was filtered, concentrated and purified by prep-HPLC [C18150 × 25 mm × 10 µm; A: water (ammonia hydroxide v / v), B: ACN, B%: 40%-70% over 10 min] to afford the title compound (96.0 mg, 77% yield) as white solid; LCMS (ESI, M+1): m / z = 696.5.

[0349] Step B. methyl 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-1,4-oxazepane-6-carboxylate: A solution of methyl 4-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxylate (50.0 mg, 1.0 equiv) in MeOH (0.9 mL) was added HCl•MeOH (2 M, 2 mL, 111 equiv) at 0 °C . The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH about 7 with NaHCO3solid, filtered and concentrated to afford the title compound (45.0 mg, 78% yield) as white solid; LCMS (ESI, M+1): m / z = 652.3.

[0350] Step C.4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepane-6-carboxylic acid: To a solution of methyl 4-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxylate (35.0 mg, 1.0 equiv) in MeOH (1 mL) was added LiOH•H2O (2 M, 1 mL, 37 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and purified by reversed-phase flash (0.1% FA condition) to afford the title compound (18.0 mg, 48% yield, HCOOH) as white solid; LCMS (ESI, M+1): m / z = 638.2.

[0351] Step D. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 4-(7-(8-ethyl-7-fluoro- 3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxylic acid (16.0 mg, 1.0 equiv, HCOOH) and 3-methyl-1H-pyrazole (5.76 mg, 3.0 equiv) and DIEA (15.1 mg, 5.0 equiv) in DMF (0.5 mL) was added HATU (17.8 mg, 2.0 equiv). The reaction was stirred at 25 °C for 2 hours. The mixture was filtered and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN, B%: 40%-70% over 9 min] to afford the title compound (4.65 mg, 26%) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.83 (t, J = 3.6 Hz, 1H), 8.11-7.98 (m, 1H), 7.67-7.52 (m, 1H), 7.23-7.09 (m, 2H), 6.84-6.62 (m, 1H), 6.29-6.17 (m, 1H), 5.43-5.20 (m, 2H), 4.51-4.31 (m, 1H), 4.28-4.17 (m, 1H), 4.04- 3.85 (m, 2H), 3.83-3.54 (m, 4H), 3.43-3.14 (m, 3H), 3.09-2.98 (m, 1H), 2.53-2.38 (m, 2H), 2.36-2.31 (m, 2H), 2.30-2.23 (m, 3H), 2.22-2.08 (m, 5H), 2.02-1.99 (m, 2H), 0.82-0.72 (m, 3H); LCMS (ESI, M+1): m / z = 702.2. EXAMPLE 78(7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octan-4- yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0352] Step A. tert-butyl 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-4,7-diazaspiro[2.5]octane-4-carboxylate: To a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (500 mg, 1.0 equiv) in DMF (6 mL) were added tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (627 mg, 3.5 equiv) and DIEA (218 mg, 2.0 equiv). The reaction was stirred at 35 °C for 10 hours. The mixture was filtered and purified by reversed phase flash [C18, 0.1 % formic acid condition] to afford the title compound (450 mg, 74% yield) as yellow solid; LCMS (ESI, M+1): m / z = 705.4.

[0353] Step B. 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(4,7-diazaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol: To a solution of tert-butyl 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (150 mg, 1.0 equiv) in MeOH (1 mL) was added HCl•MeOH (2 M, 3 mL) at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was adjusted to pH=7 with saturated NaHCO3 (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (120 mg, crude) as white solid.

[0354] Step C. (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octan-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 3-methyl- 1H-pyrazole (20.0 mg, 1.0 equiv) and DIEA (126 mg, 4.0 equiv) in DCM (0.5 mL) was added bis(trichloromethyl) carbonate (120 mg, 1.7 equiv). The reaction was stirred at 0 °C for 1 hour. To the mixture were added 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(4,7-diazaspiro[2.5]octan-7-yl)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (118 mg, 0.8 equiv) and DIEA (47.2 mg, 1.5 equiv) in DCM (0.5 mL) at 0 °C. The reaction was stirred at 20 °C for 12 hours. The mixture was quenched with saturated NaHCO3aqueous (10 mL) and extracted with DCM (4 × 10 mL). The combined organic layers were washed with brine(20 mL), dried over anhydrous sodium sulfate, concentrated and purified prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 µm; A: water(FA), B: ACN; B%: 20%-50% over 10 min] and SFC [column: DAICEL CHIRALCEL OX (250 mm × 30 mm, 10 µm); A: CO2-ACN, B: MeOH (0.1% NH3•H2O); B%: 40%, isocratic elution mode] to afford two peaks.

[0355] Peak 1: (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7- diazaspiro[2.5]octan-4-yl)(5-methyl-1H-pyrazol-1-yl)methanone : The residue was purified prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 µm; A: water(FA), B: ACN; B%:22%-52% over 10 min] to afford the title compound (6.63 mg, 3.8% yield) as off-white gum;1H NMR (400 MHz, DMSO-d6) δ = 10.00 (s, 1H), 9.16 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.54 (s, 1H), 7.41-7.29 (m, 2H), 7.04 (d, J = 2.4 Hz, 1H), 6.26 (s, 1H), 5.59-5.34 (m, 1H), 4.41-4.14 (m, 6H), 3.89 (br d, J = 3.6 Hz, 2H), 3.46 (br d, J = 6.8 Hz, 2H), 2.44-1.84 (m, 13H), 1.02-0.78 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 713.3; SFC: 96.3% de, Column: Chiralcel OX-350 × 4.6 mm I.D., 3 µm Mobile phase: Phase A for CO2, and Phase B for MeOH+ACN(0.05%DEA); Gradient elution: 30% MeOH+ACN (0.05% DEA) in CO2 Flow rate: 3mL / min; Detector: PDA Column Temp: 35C;Back Pressure: 100Bar, tR: 2.315 min.

[0356] Peak 2 : (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octan-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone : The residue was purified prep-HPLC [column: Phenomenex luna C18150 × 25 mm × 10 µm; A: water(FA), B: ACN; B%: 22%-52% over 10 min] to afford the title compound (11.8 mg, 6.6% yield) as off-white gum;1H NMR (400 MHz, DMSO-d6) δ = 10.03 (br s, 1H), 9.13 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 6.0, 8.8 Hz, 1H), 7.39-7.28 (m, 2H), 7.05 (s, 1H), 6.31 (d, J = 2.4 Hz, 1H), 5.47-5.26 (m, 1H), 4.32-4.08 (m, 8H), 2.97 (br d, J = 5.2 Hz, 2H), 2.33 (br s, 2H), 2.26-1.76 (m, 11H), 1.05-0.95 (m, 2H), 0.90 (br s, 2H), 0.71 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 713.3; SFC: 97.3% de, Column: Chiralcel OX-350 × 4.6 mm I.D., 3 µm Mobile phase: Phase A for CO2, and Phase B for MeOH+ACN(0.05%DEA); Gradient elution: 30% MeOH+ACN (0.05% DEA) in CO2Flow rate: 3mL / min; Detector: PDA Column Temp: 35C;Back Pressure: 100Bar, tR: 2.765 min. EXAMPLE 79((3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0357] Step A. cis-1-benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate: To a solution of cis-methyl (3R,4R)-3-methylpiperidine-4-carboxylate (800 mg, 1.0 equiv) and TEA (1.54 g, 3.0 equiv) in DCM (16 mL) was added benzyl carbonochloridate (1.04 g, 1.2 equiv). The reaction was stirred at 0 °C for 1 hour. The mixture was concentrated and purified by silica gel chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 10 / 1) to afford the title compound (1.1g, 69% yield) as white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.46- 7.23 (m, 5H), 5.07 (s, 2H), 3.91 (br d, J = 13.2 Hz, 1H), 3.72 (br d, J = 12.0 Hz, 1H), 3.61 (s, 3H), 3.23-3.06 (m, 1H), 3.02-2.80 (m, 1H), 2.71 (td, J = 4.8, 10.0 Hz, 1H), 2.15 (br dd, J = 3.6, 6.8 Hz, 1H), 1.73-1.50 (m, 2H), 0.75 (d, J = 6.8 Hz, 3H).

[0358] Step B. 1-benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate: methyl (3R,4R)-3-methylpiperidine-4-carboxylate (1.3 g, 1.0 equiv) was purified by SFC separation [column: DAICEL CHIRALPAK AD, 250 mm × 50mm, 10 µm; A: CO2, B: MeOH(0.2% NH3H2O), B%: 15% B over 6.3 min] to afford two isomers.

[0359] peak 1: 1-benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate (700 mg, 50% yield) as white solid; LCMS (ESI, M-44): m / z = 248.4; SFC >99% ee, column: Chiralpak AD-350 × 4.6 mm I.D., 3 µm; mobile phase: 5% to 40% MeOH (0.05%DEA) in CO2, flow rate: 3 mL / min, detector: PDA, tR: 1.054 min.

[0360] peak 2:1-benzyl 4-methyl (3S,4S)-3-methylpiperidine-1,4-dicarboxylate (700 mg, 51% yield) as white solid; LCMS (ESI, M-44): m / z = 248.4; SFC >99% ee, column: Chiralpak AD-350 × 4.6 mm I.D., 3 µm; mobile phase: 5% to 40% MeOH (0.05%DEA) in CO2, flow rate: 3 mL / min, detector: PDA, tR: 1.162 min.

[0361] Step C. methyl (3R,4R)-3-methylpiperidine-4-carboxylate: To a solution of 1- benzyl 4-methyl (3R,4R)-3-methylpiperidine-1,4-dicarboxylate (600 mg, 1.0 equiv) in MeOH (12 mL) was added Pd / C (60 mg, 10% purity). The reaction was degassed and purged with nitrogen 3 times. The reaction was stirred at 25 °C for 2 hours under H2 atmosphere (15 Psi). The mixture was filtered and concentrated to afford the title compound (300 mg, crude) as yellow oil;1H NMR (400 MHz, DMSO-d6) δ = 3.58 (s, 3H), 2.87 (td, J = 4.0, 12.2 Hz, 1H), 2.66 (br dd, J = 3.6, 6.0 Hz, 2H), 2.56 (td, J = 4.4, 10.8 Hz, 1H), 2.45-2.34 (m, 1H), 2.03-1.91 (m, 1H), 1.66-1.38 (m, 2H), 0.85 (d, J = 6.8 Hz, 3H).

[0362] Step D. methyl (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3-methylpiperidine-4-carboxylate: To a solution of 5-ethyl-6-fluoro-4-(8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (150 mg, 1.0 equiv), methyl (3R,4R)-3-methylpiperidine-4-carboxylate (47.8 mg, 1.2 equiv) in DMAC (2 mL) were added K3PO4 (161 mg, 3.0 equiv) and 4Å molecular sieve (30.0 mg). The reaction was stirred at 60 °C for 0.5 hours. The mixture was filtered and filtrate was diluted with H2O (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (200 mg, crude) as yellow solid; LCMS (ESI, M+1): m / z = 650.4.

[0363] Step E. (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-methylpiperidine-4-carboxylic acid: To a solution of methyl (3R,4R)-1-(7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-4-carboxylate (200 mg, 1.0 equiv) in MeOH (2 mL) were added LiOH•H2O (2 M, 2.00 mL, 13 equiv). The reactionwas stirred at 25 °C for 0.5 hours. The mixture was purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (100 mg, 44% yield) as white solid; LCMS (ESI, M+1): m / z = 636.5.

[0364] Step F. ((3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of (3R,4R)- 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-4- carboxylic acid (90.0 mg, 1.0 equiv) and HATU (161 mg, 3.0 equiv) in DMF (1 mL) were added 3-methyl-1H-pyrazole (17.4 mg, 1.5 equiv) and DIEA (91.5 mg, 5.0 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3); B: ACN, B%: 55%-85% over 9 min] to afford the title compound (10 mg, 10% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.00 (br d, J = 4.0 Hz, 1H), 8.22-8.13 (m, 1H), 7.64-7.50 (m, 1H), 7.23-7.16 (m, 2H), 7.13-6.95 (m, 1H), 6.36-6.18 (m, 1H), 5.48-5.12 (m, 1H), 4.49-4.23 (m, 3H), 4.21-4.13 (m, 1H), 3.91 (br dd, J = 2.4, 12.8 Hz, 1H), 3.83-3.65 (m, 1H), 3.46-3.09 (m, 3H), 3.06-2.91 (m, 1H), 2.75-2.57 (m, 1H), 2.56-2.40 (m, 1H), 2.39-2.29 (m, 4H), 2.24 (br s, 1H), 2.14 (br dd, J = 3.8, 8.2 Hz, 2H), 2.00-1.84 (m, 6H), 1.04-0.92 (m, 3H), 0.82 (q, J = 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 700.5. EXAMPLE 80(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(4-isopropyl- 1H-pyrazol-1-yl)methanone

[0365] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin- 4-yl)(4-isopropyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (80.0 mg, 1.0 equiv) and 4-isopropyl-1H-pyrazole (42.5 mg, 3.0 equiv) in DMF (1 mL) was added HATU (73.4 mg, 1.5 equiv) and DIEA (49.9 mg, 3.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was filtered and purified by prep-HPLC [column: Waters Xbridge 150 × 25 mm× 5 μm; A: water (NH4HCO3), B: ACN, B%: 62%-92% over 15 min]. The aqueous was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (4.79 mg, 15% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.99 (s, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 7.58 (dd, J = 5.6, 9.2 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.05 (dd, J = 2.4, 18.4 Hz, 1H), 5.43 - 5.20 (m, 1H), 4.73 - 4.58 (m, 2H), 4.35 - 4.27 (m, 2H), 4.10 - 3.98 (m, 1H), 3.58 - 3.46 (m, 2H), 3.41 - 3.14 (m, 3H), 3.08 - 2.95 (m, 1H), 2.91 - 2.83 (m, 1H), 2.57 - 2.44 (m, 1H), 2.39 - 2.30 (m, 1H), 2.27 - 2.08 (m, 7H), 2.04 - 1.92 (m, 3H), 1.26 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 6.8 Hz, 3H); LCMS (ESI, M+1): m / z = 714.4. EXAMPLE 81((2S,6R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6- dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0366] Step A. tert-butyl (3R,5S)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate: To a solution of 3-methyl-1H-pyrazole (192 mg, 1.0equiv) in DCM (3 mL) were added bis(trichloromethyl) carbonate (410 mg, 0.59 equiv) and TEA (472 mg, 2.0 equiv) at 0 °C slowly. The reaction was stirred at 0 °C for 2 hours. tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (500 mg, 1.0 equiv) and TEA (472 mg, 2.0 equiv) in DCM (3 mL) were added at 0 °C. The reaction was stirred at 40 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 1 / 1) to afford the title compound (500 mg, 88%) as white oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.00 (d, J = 2.4 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 4.82 (br d, J = 2.4 Hz, 2H), 4.06-3.81 (m, 2H), 3.29-3.03 (m, 2H), 2.30 (s, 3H), 1.50 (s, 9H), 1.38 (d, J = 7.2 Hz, 6H); LCMS (ESI, M+23): m / z = 345.1.

[0367] Step B. ((2R,6S)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1- yl)methanone: To a solution of tert-butyl (3R,5S)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate (400 mg, 1.0 equiv) in HCl•MeOH (2 M, 8.00 mL, 12.9 equiv) was stirred at 25 °C for 1 hour. The mixture was concentrated, dissolved with MeOH (5 mL), adjusted to pH = 7 with NaHCO3solid, concentrated under reduced pressure to dryness. The mixture was dissolved with DCM (5 mL) and filtered. The filtrate was concentrated under reduced pressure to dryness to afford the title compound (300 mg, crude) as white oil; LCMS (ESI, M+1): m / z = 223.2.

[0368] Step C. ((2R,6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (600 mg, 1.0 equiv) in DMF (6 mL) were added PYBOP (845 mg, 1.5 equiv) and DIEA (420 mg, 3.0 equiv) . The reaction was stirred at 25 °C for 0.5 hours. ((2R,6S)-2,6-dimethylpiperazin-1- yl)(3-methyl-1H-pyrazol-1-yl)methanone (289 mg, 1.2 equiv) was added into the mixture. The reaction was stirred at 25 °C for 1.5 hours. The reaction mixture was quenched by addition of water (15 mL) at 0 °C and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with saturated brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by prep-HPLC [Waters Xbridge Prep OBD C18150 × 40mm × 10 μm; A: water (NH4HCO3), B%: ACN, B%: 55%-85% over 20 min] to afford the title compound (500 mg, 99% yield) as white solid; LCMS (ESI, M+1): m / z = 759.4.

[0369] Step D. ((2R,6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: A solution of ((2R,6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6- dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone (150 mg, 1.0 equiv) in HCl•MeOH (2 M, 3.00 mL, 30 equiv) was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved with MeOH (3 mL), adjusted to pH = 7 with NaHCO3 solid, filtered, concentrated and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B%: ACN, B%: 52%-82% over 9 min] to afford the title compound (55.3 mg, 96% yield) as white solid;1H NMR (400 MHz, DMSO- d6) δ = 9.92 (s, 1H), 9.22 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.43- 7.29 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 6.33 (d, J = 2.8 Hz, 1H), 5.42-5.13 (m, 1H), 4.66 (br s, 2H), 4.36-4.21 (m, 2H), 4.20-4.14 (m, 1H), 4.12-3.98 (m, 3H), 3.15-2.96 (m, 3H), 2.88-2.76 (m, 1H), 2.40-2.31 (m, 1H), 2.25 (s, 3H), 2.18-1.98 (m, 4H), 1.77 (br s, 3H), 1.54-1.37 (m, 6H), 0.73 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 715.4. EXAMPLE 82(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)(3- methyl-1H-pyrazol-1-yl)methanone

[0370] Step A. tert-butyl 3-methyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1- carboxylate: To a solution of 3-methyl-1H-pyrazole (205 mg, 1.0 equiv) in DCM (3 mL) was added bis(trichloromethyl) carbonate (490 mg, 0.66 equiv) and TEA (505 mg, 2.0 equiv) at 0 °C. The reaction was stirred at 0 °C for 3 hours. Tert-butyl 3-methylpiperazine-1-carboxylate (500 mg, 1.0 equiv) and TEA (505 mg, 2.0 equiv) in DCM (3 mL) were added at 0 °C. The reaction was stirred at 40 °C for 2 hours. The mixture was quenched with water (5 mL) and extracted with dichloromethane (3 × 10 mL). The organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford the title compound (280 mg, 34% yield) as colorless oil;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.05-7.92 (m, 1H), 6.13 (d, J = 2.8 Hz, 1H), 4.78 (br s, 1H), 4.41 (br d, J = 12.4 Hz, 1H), 4.18-4.03 (m, 1H), 3.95-3.74 (m, 1H), 3.32 (dt, J = 3.6, 12.0 Hz, 1H), 3.21-2.88 (m, 2H), 2.28 (s, 3H), 1.46 (s, 9H), 1.30 (d, J = 6.8 Hz, 3H); LCMS (ESI, M+23): m / z = 331.1.

[0371] Step B. (3-methyl-1H-pyrazol-1-yl)(2-methylpiperazin-1-yl)methanone: A solution of tert-butyl 3-methyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate (230 mg, 1.0 equiv) in HCl•MeOH (2 M, 4.6 mL, 12.3 equiv) was stirred at 25 °C for 2 hours. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH about 7 with NaHCO3solid, filtered and concentrated to afford the title compound (153 mg, 97% yield) as white solid; LCMS (ESI, M+1): m / z = 209.2.

[0372] Step C. (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 7-(8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (380 mg, 1.0 equiv) in DMF (6 mL) were added DIEA (266 mg, 3.0 equiv) and PyBOP (535 mg, 1.5 equiv) slowly at 25 °C, the reaction was stirred at 25 °C for 20 minutes. (3-methyl-1H-pyrazol-1- yl)(2-methylpiperazin-1-yl)methanone (150 mg, 1.0 equiv) was added at 25 °C slowly. The reaction was stirred at 25 °C for 2 hours. The mixture was filtered and purified by reversed- phase flash (0.1% FA condition) to afford the title compound (700 mg, crude, HCOOH) as colorless oil; LCMS (ESI, M+1): m / z = 745.4.

[0373] Step D. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2- methylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: A solution of (4-(7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)(3- methyl-1H-pyrazol-1-yl)methanone (300 mg, 1.0 equiv, HCOOH) in HCl•MeOH (2 M, 5 mL,26 equiv) was stirred at 25 °C for 2 hours. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH about 7 with NaHCO3 solid, filtered, concentrated and purified by prep-HPLC [Waters Xbridge Prep OBD C18150 × 40 mm × 10 µm; A: water (NH4HCO3), B: ACN, B%: 40%-70% over 20 min] to afford the title compound (81.0 mg, 30% yield over two steps) as white solid;1H NMR (400 MHz, DMSO-d6) δ = 10.04-9.82 (m, 1H), 9.20 (s, 1H), 8.13 (t, J = 2.4 Hz, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.43-7.28 (m, 2H), 7.13-6.94 (m, 1H), 6.33 (d, J = 2.8 Hz, 1H), 5.44-5.16 (m, 1H), 4.85-4.65 (m, 1H), 4.51-4.39 (m, 1H), 4.39- 4.25 (m, 2H), 4.21-3.97 (m, 3H), 3.96-3.83 (m, 2H), 3.30-3.24 (m, 1H), 3.15-3.06 (m, 2H), 2.89-2.74 (m, 1H), 2.43-2.32 (m, 1H), 2.25 (s, 3H), 2.19-1.96 (m, 4H), 1.77 (br s, 3H), 1.37 (dd, J = 6.8, 10.0 Hz, 3H), 0.79-0.65 (m, 3H); LCMS (ESI, M+1): m / z = 701.3. EXAMPLE 83(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-yl)(3- methyl-1H-pyrazol-1-yl)methanone

[0374] Step A. methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-4-methylpiperidine-4-carboxylate: To a solution of 7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (2.3 g, 1.0 equiv) and methyl 4- methylpiperidine-4-carboxylate (1.0 g, 1.2 equiv, HCl salt) in DMF (20 mL) were added PyBOP (3.24 g, 1.5 equiv) and DIEA (5.36 g, 10 equiv). The reaction was stirred at 25 °C for12 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (3.4 g, 87% yield) as yellow solid; LCMS (ESI, M+1): m / z = 694.4.

[0375] Step B. methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-4-methylpiperidine-4-carboxylate: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidine-4-carboxylate (3.4 g, 1.0 equiv) in MeOH (15 mL) was added HCl•MeOH (2 M, 30 mL, 12 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated. The residue was basified with saturated NaHCO3 solution (80 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reversed phase flash chromatography [C18, 0.1% NH3•H2O condition] to afford the title compound (1.9 g, 55% yield) as white solid; LCMS (ESI, M+1): m / z = 650.4.

[0376] Step C.1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- methylpiperidine-4-carboxylic acid: To a solution of methyl 1-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidine-4-carboxylate (1.9 g, 1.0 equiv) in MeOH (15 mL) was added LiOH•H2O (2 M in H2O, 15 mL, 10 equiv). The reaction was stirred at 25 °C for 4 hours. The mixture was filtered and the filtrate was purified by reversed phase flash chromatography [C18, 0.1% formic acid condition] to afford the title compound (1.12 g, 34% yield) as yellow solid; LCMS (ESI, M+1): m / z = 636.4.

[0377] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4- methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 1-(7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidine-4-carboxylic acid (300 mg, 1.0 equiv) and 3-methyl-1H-pyrazole (58.1 mg, 1.5 equiv) in DMF (3 mL) were added HATU (359 mg, 2.0 equiv) and DIEA (366 mg, 6.0 equiv). The reaction was stirred at 25 °Cfor 12 hours. The mixture was filtered purified by prep-HPLC [Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; A: water (NH4HCO3), B: ACN, B%: 52%-82% over 20 min] to afford the title compound (8.22 mg, 2.4% yield) as yellow solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.93 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H), 7.56-7.48 (m, 1H), 7.20-7.10 (m, 2H), 7.01-6.88 (m, 1H), 6.22 (d, J = 2.8 Hz, 1H), 5.40-5.17 (m, 1H), 4.34-4.18 (m, 4H), 3.75-3.59 (m, 2H), 3.36-3.11 (m, 3H), 3.04-2.93 (m, 1H), 2.89-2.76 (m, 2H), 2.50- 2.41 (m, 1H), 2.33 (s, 3H), 2.27-2.12 (m, 4H), 1.97-1.89 (m, 5H), 1.64 (br d, J = 1.1 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H); LCMS (ESI, M+1): m / z = 700.4. EXAMPLE 842-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)-1-(3-methyl-1H-pyrazol-1-yl)ethan-1-oneStep A. 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3- yl)acetic acid: To a solution of 2-(azetidin-3-yl)acetic acid (154 mg, 2 equiv, HCl), DIEA (327 mg, 5.0 equiv) in DMF (3.00 mL) was added 4Å molecular sieve (20 mg). The reaction was stirred at 25 °C for 10 minutes. Then 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (300 mg, 1.0 equiv) was added. The reaction was stirred at 40 °C for 3 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (320 mg, 96% yield, HCOOH) as white solid;1H NMR (400 MHz, DMSO-d6) δ 10.25-9.58 (m, 1H), 8.93 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.41-7.27 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 5.46-5.22 (m, 1H), 5.06-4.89 (m, 1H), 4.62-4.38 (m, 2H), 4.28-3.96 (m, 4H), 3.23-3.08 (m, 5H), 2.95- 2.85 (m, 1H), 2.76 (br d, J = 7.2 Hz, 2H), 2.43-2.28 (m, 1H), 2.22-1.98 (m, 4H), 1.94-1.74 (m, 3H), 0.78-0.63 (m, 3H); LCMS (ESI, M+1): m / z = 608.3.

[0378] Step B. 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)azetidin-3-yl)-1-(3-methyl-1H-pyrazol-1-yl)ethan-1-one: To a solution of 2-(1-(7-(8-ethyl- 7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azetidin-3-yl)acetic acid (100 mg, 1.0 equiv) and HATU (93.9 mg, 1.5 equiv) in DMF (1.00 mL) was added DIEA (106 mg, 5.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. Then 3-methyl-1H-pyrazole (27.0 mg, 2.0 equiv) was added into the reaction mixture. The reaction was stirred at 25 °C for 0.5 hours. The mixture was filtered and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water( NH4HCO3), B: ACN; B%: 45%-75% B over 9 min] to afford the title compound (5.05 mg, 4.2% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.79 (s, 1H), 8.15 (d, J = 2.8 Hz, 1H), 7.60-7.49 (m, 1H), 7.21-7.09 (m, 2H), 6.97-6.78 (m, 1H), 6.30 (d, J = 2.8 Hz, 1H), 5.42-5.18 (m, 1H), 5.03-4.51 (m, 2H), 4.45-4.07 (m, 4H), 3.57-3.14 (m, 6H), 3.09- 2.95 (m, 1H), 2.54-2.41 (m, 1H), 2.34 (d, J = 1.2 Hz, 3H), 2.31-2.21 (m, 2H), 2.19-2.07 (m, 3H), 1.96 (br s, 2H), 0.80 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 672.2. EXAMPLE 85((3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0379] Step A. methyl (3S,4S)-3-methylpiperidine-4-carboxylate: To a solution of 1-benzyl 4-methyl (3S,4S)-3-methylpiperidine-1,4-dicarboxylate (700 mg, 1.0 equiv) in MeOH (14 mL) was added Pd / C (70 mg, 10% purity). The reaction was degassed and purged with nitrogen 3 times and stirred at 25 °C for 2 hours under H2 atmosphere (15 Psi). The mixture was filtered and concentrated to afford the title compound (350 mg, crude) as yellow oil;1H NMR (400 MHz, DMSO-d6) δ = 3.59 (s, 3H), 2.88 (td, J = 4.0, 12.0 Hz, 1H), 2.73-2.62 (m, 2H), 2.57 (td,J = 4.4, 10.8 Hz, 1H), 2.46-2.39 (m, 1H), 2.00 (tdd, J = 3.2, 7.2, 10.4 Hz, 1H), 1.71-1.39 (m, 2H), 0.85 (d, J = 7.2 Hz, 3H).

[0380] Step B. methyl (3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3-methylpiperidine-4-carboxylate: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (500 mg, 1.0 equiv) and methyl (3S,4S)-3-methylpiperidine-4-carboxylate (199 mg, 1.5 equiv) in DMF (10 mL) were added K3PO4(537 mg, 3.0 equiv) and 4Å molecular sieve (100 mg). The reaction was stirred at 60 °C for 0.5 hours. The mixture was filtered, diluted with H2O (50 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated to afford the title compound (400 mg, crude) as yellow solid; LCMS (ESI, M+1): m / z = 650.5.

[0381] Step C. (3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-methylpiperidine-4-carboxylic acid: To a solution of methyl (3S,4S)-1-(7-(8-ethyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-4-carboxylate (400 mg, 1.0 equiv) in MeOH (4 mL) were added LiOH•H2O (2 M, 4.00 mL, 13 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and purified by reversed phase flash chromatography[C18, 0.1 % formic acid condition] to afford the title compound (250 mg, 63% yield) as white solid; LCMS (ESI, M+1): m / z = 636.3.

[0382] Step D. ((3S,4S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-3-methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of (3S,4S)-1- (7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-4- carboxylic acid (250 mg, 1.0 equiv) and HATU (449 mg, 3.0 equiv) in DMF (3 mL) were added 3-methyl-1H-pyrazole (17.4 mg, 1.5 equiv) and DIEA (254 mg, 5.0 equiv). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and purified by prep-HPLC [WatersXbridge Prep OBD C18150 × 40 mm × 10 µm; A: water (NH4HCO3); B: ACN, B%: 46%- 76% over 20 min] to afford the title compound (11 mg, 4% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.00 (s, 1H), 8.17 (t, J = 3.2 Hz, 1H), 7.59-7.51 (m, 1H), 7.24- 7.16 (m, 2H), 7.09-6.99 (m, 1H), 6.29 (t, J = 2.2 Hz, 1H), 5.41-5.18 (m, 1H), 4.47-4.25 (m, 3H), 4.22-4.12 (m, 1H), 3.97-3.84 (m, 1H), 3.82-3.65 (m, 1H), 3.35-3.13 (m, 3H), 3.05-2.95 (m, 1H), 2.70-2.59 (m, 1H), 2.55-2.42 (m, 1H), 2.38-2.28 (m, 4H), 2.23 (br s, 1H), 2.20-2.09 (m, 2H), 2.05-1.82 (m, 6H), 1.08-0.91 (m, 3H), 0.89-0.75 (m, 3H); LCMS (ESI, M+1): m / z = 700.3. EXAMPLE 86((2R,6R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6- dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0383] Step A. tert-butyl (3R,5R)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate: To a solution of 3-methyl-1H-pyrazole (190 mg, 1.0 equiv) and TEA (468 mg, 2.0 equiv) in DCM (3 mL) was added bis(trichloromethyl) carbonate (130 mg, 0.19 equiv) at 0 °C. The reaction was stirred at 0 °C for 2 hours. Tert-butyl (3R,5R)- 3,5-dimethylpiperazine-1-carboxylate (496 mg, 1.0 equiv) and TEA (468 mg, 2.0 equiv) in DCM (2 mL) were added. The reaction was stirred at 25 °C for 2 hours. The mixture was quenched with water (5 mL) and extracted with dichloromethane (3 × 10 mL). The organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to afford the title compound (60.0 mg, 7.6% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 8.08 (d, J = 2.8 Hz, 1H), 6.15 (d, J = 2.8 Hz, 1H), 4.81 (br s, 2H), 3.69-3.54 (m, 4H), 2.31 (s, 3H), 1.49 (s, 9H), 1.32 (d, J = 6.8 Hz, 6H); LCMS (ESI, M+1): m / z = 323.4.

[0384] Step B. ((2R,6R)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1- yl)methanone: A solution of tert-butyl (3R,5R)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1- carbonyl)piperazine-1-carboxylate (50 mg, 1.0 equiv) in HCl•MeOH (2 M, 64 equiv) was stirred at 0 °C for 1 hour. The mixture was concentrated, diluted with MeOH (3 mL), adjustedto pH about 8 with NaHCO3 solid, filtered and concentrated to afford the title compound (50.0 mg, crude) as yellow oil; LCMS (ESI, M+1): m / z = 223.1.

[0385] Step C. ((2R,6R)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of ((2R,6R)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone (40.1 mg, 1.0 equiv) and 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4- ol (100 mg, 1.0 equiv) in DMF (1 mL) were added DIEA (93.2 mg, 4.0 equiv) and HATU (137 mg, 2.0 equiv). The reaction was stirred at 25 °C for 0.5 hours. The mixture was filtered and purified by prep-HPLC [C18150 × 30 mm; A: water (FA), B: ACN, B%: 25%-55% over 7 min] to afford the title compound (60.0 mg, 38% yield, HCOOH) as brown solid; LCMS (ESI, M+1): m / z = 759.4.

[0386] Step D. ((2R,6R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: A solution of ((2R,6R)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone (50.0 mg, 1.0 equiv, HCOOH) in HCl•MeOH (2 M, 121 equiv) was stirred at 25 °C for 0.5 hours. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH about 8 with NaHCO3 solid, filtered, concentrated and purified by prep-HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 25%-55% over 9 min] and prep-HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3); B: ACN, B%: 52%-82% over 9 min] to afford the title compound (10.0 mg, 34% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.07 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.56 (td, J = 6.4, 9.2 Hz, 1H), 7.24-7.14 (m, 2H), 7.08- 6.93 (m, 1H), 6.18 (t, J = 2.8 Hz, 1H), 5.48-5.15 (m, 3H), 4.48-4.29 (m, 3H), 4.28-4.18 (m, 1H), 4.14-3.98 (m, 2H), 3.33-3.08 (m, 3H), 3.04-2.92 (m, 1H), 2.61-2.40 (m, 1H), 2.32 (d, J = 7.6 Hz, 4H), 2.10 (br t, J = 8.4 Hz, 3H), 2.03-1.87 (m, 3H), 1.43 (dd, J = 4.8, 6.4 Hz, 6H), 0.83 (q, J = 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 715.4.EXAMPLE 87(6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octan-1- yl)(3-methyl-1H-pyrazol-1-yl)methanone

[0387] Step A.6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- azabicyclo[3.2.1]octane-1-carboxylic acid: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (300 mg, 1.0 equiv) and 6- azabicyclo[3.2.1]octane-1-carboxylic acid (194 mg, 2.0 equiv, HCl) in DMF (2.5 mL) were added DIEA (261 mg, 4.0 equiv) and K3PO4(322 mg, 3.0 equiv). The reaction was stirred at 60 °C for 0.5 hours. The mixture was filtered and purified by reversed phase flash chromatography [C18, 0.1 % formic acid condition] to afford the title compound (210 mg, 63% yield, HCOOH salt) as white solid; LCMS (ESI, M+1): m / z = 648.3.

[0388] Step B. (6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- azabicyclo[3.2.1]octan-1-yl)(3-methyl-1H-pyrazol-1-yl)methanone: To a solution of 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octane-1- carboxylic acid (50 mg, 1.0 equiv) and 3-methyl-1H-pyrazole (31.7 mg, 5 equiv) in DMF (0.5 mL) were added HATU (58.7 mg, 2.0 equiv) and DIEA (59.9 mg, 6.0 equiv). The reaction was stirred at 25 °C for 20 mins. The mixture was filtered and purified by reversed phase flash chromatography [C18,water / ACN] to afford the title compound (4.77 mg, 8% yield) as white solid;1H NMR (400 MHz, CHLOROFORM-d) δ = 9.38-9.20 (m, 1H), 8.21-8.09 (m, 1H), 7.58-7.46 (m, 1H), 7.22-6.98 (m, 3H), 6.25 (br s, 1H), 5.46-5.04 (m, 2H), 4.92-4.72 (m, 1H), 4.42-4.18 (m, 3H), 3.42-3.13 (m, 3H), 3.05-2.91 (m, 1H), 2.46 (br d, J = 11.2 Hz, 3H), 2.36- 2.22 (m, 6H), 2.12 (br d, J = 2.0 Hz...

Claims

WE CLAIM:

1. A compound of Formula (Ia) or (Ib): Z Y D A R9(1-4)R13E N R6R6R3N O B R4Formula (Ia) Formula (Ib) or a pharmaceutically acceptable salt thereof, wherein: X N N A is selected from: , , , , NH ,NH N NHNH, , , , , , and B is selected from: , , ; X is a bond, N, methylene, ethylene or propylene; D is CO or SO2; E is N or CR10;Y is a bond, O or NR5; Z is hydrogen, C1-C4 alkyl, heterocyclyl, heteroaryl or aryl, where Z is optionally substituted with 1-3 substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, oxo, OR12, N(R12)2, COR12and cyano; each R2is independently hydrogen, hydroxy, halogen, C1-C3 alkyl, spiro cyclopropyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF2, HC(=O)-, -OC(O)N(R5)2, -CO2R5, -CO2N(R5)2, =CH2, =CHR11or =C(R11)2, wherein R2is optionally substituted with one or more R4; R3is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted with one or more R8; R4is hydrogen, halogen or C1 – C3 alkyl; each R5is independently hydrogen or C1 – C3 alkyl; each R6is independently hydrogen, hydroxy, C1-C4 alkyl, C1-C4 hydroxyalkyl or heteroaryl, or two R6join to form C3-C6 cycloalkyl or heterocycle; each R8is independently halogen, cyano, hydroxy, cycloalkyl, C1 - C3 alkyl, -S-C1 - C3 alkyl, C2 – C4 alkenyl, C2 – C4 alkynyl, C2 – C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1 - C3 haloalkyl, -O- C1 - C3 haloalkyl, or -S- C1 - C3 haloalkyl; each R9is independently hydrogen, C1-C4 alkyl, methoxy, CH2-methoxy, hydroxy, CH2F, CF2, CF3, C-CN, cyclopropyl, or two R9on the same or different carbon atoms join to form a C1-C2 alkylene bridge or a spirocycle; each R10is hydrogen, halogen, CH2F, CHF2, CF3, C1–C3 alkyl, cyclopropyl, OR12, or N(R12)2; each R11is halogen or C1-C3 alkyl, R12is C1-C3 alkyl, and R13is H or forms a ring with A.

2. The compound or salt according to claim 1, wherein Formula (Ia) is Formula IA:(Formula IA).

3. The compound or salt according to claim 1, wherein Formula (Ia) is Formula IB:(Formula IB).

4. The compound or salt according to any of claims 1-3, wherein B is:

5. The compound or salt according to any of claims 1-4, wherein X is methylene.

6. The compound or salt according to any of claims 1-4, wherein X is ethylene.

7. The compound or salt according to any of claims 1-4, wherein X is a bond.

8. The compound or salt according to any of claims 1-4, wherein X is propylene.

9. The compound or salt according to any of claims 1-8, wherein Y is O.

10. The compound or salt according to any of claims 1-8, wherein Y is NR5.

11. The compound or salt according to any of claims 1-8, wherein Y is a bond.

12. The compound or salt according to any of claims 1-8, wherein Z is hydrogen.

13. The compound or salt according to any of claims 1-8, wherein Z is C1-C4 alkyl, optionally substituted with 1-3 halogens.

14. The compound or salt according to any of claims 1-8, wherein Z is aryl, optionally substituted with 1-3 halogens, cyano, or C1-C4 haloalkyl.

15. The compound or salt of claim 14, wherein said aryl is phenyl.

16. The compound or salt according to any of claims 1-8, wherein Z is heteroaryl, optionally substituted with 1-2 C1-C4 alkyl.

17. The compound or salt of claim 16, wherein said heteroaryl is pyrazolyl or pyridinyl.

18. The compound or salt according to any of claims 1-8, wherein Z is heterocyclyl, optionally substituted with oxo.

19. The compound or salt of claim 18, wherein said heterocyclyl is oxazolidine.

20. The compound or salt according to any of claims 1-8, wherein two R9join to form a methylene bridge.

21. The compound or salt according to any of claims 1-8, wherein two R9join to form an ethylene bridge.

22. The compound or salt according to claim 4, wherein R2is fluoro.

23. The compound or salt according to claim 19, wherein R2is =CHR11.

24. The compound or salt according to claim 19, wherein R2is =C(R11)2.

25. The compound or salt according to any one of claims 1-24, wherein R3is aryl optionally substituted with one or more R8.

26. The compound or salt according to claim 25, wherein the aryl is naphthyl optionally substituted with one or more R8.

27. The compound or salt according to claim 26, wherein the naphthyl is substituted with one R8, wherein the one R8is hydroxy, halogen, C1 – C3 alkyl, C1 -C3 haloalkyl, cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl.

28. The compound or salt according to claim 26, wherein the naphthyl is substituted with two R8, wherein one R8is hydroxy and the other R8is C1 – C3 alkyl, halogen or C2-C4 alkynyl, or one R8is halogen and the other R8is C1 – C3 alkyl or C2-C4 alkynyl.

29. The compound or salt according to claim 26, wherein the naphthyl is substituted with three R8, wherein the first R8is hydroxy, the second R8is halogen and the third R8is C1 – C3 alkyl or C2-C4 alkynyl.

30. The compound or salt according to claim 26, wherein the aryl is phenyl optionally substituted with one or more R8.

31. The compound or salt according to claim 30, wherein the phenyl is substituted with one R8, wherein the R8is C1 – C3 alkyl.

32. The compound or salt according to claim 30, wherein the phenyl is substituted with two R8, wherein one R8is halogen and the other R8is C1 – C3 alkyl.

33. The compound or salt according to claim 30, wherein the phenyl is substituted with two R8, wherein one R8is halogen and the other R8is cycloalkyl.

34. The compound or salt according to any one of claims 1-24, wherein R3is heteroaryl.

35. The compound or salt according to claim 34, wherein the heteroaryl is indazolyl optionally substituted with one or more R8.

36. The compound or salt according to claim 35, wherein the indazolyl is substituted with two R8, wherein one R8is halogen and the other R8is C1 – C3 alkyl.

37. The compound or salt according to any one of claims 1-36, wherein R4is halogen.

38. The compound or salt according to claim 37, wherein the halogen is fluorine.

39. The compound or salt of claim 1, wherein the compound is selected from, , ,N N O F N F N N , , ,, , ,, , ,, , ,, , ,, ,, , , ,, , , ,N, , ,, , ,N N O H2NNHN , H2N , ,, , , , , ,, ,,, , ,, , ,,,, ,and pharmaceutically acceptable salts thereof.

40. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

41. A method for inhibiting KRas G12S and / or KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12S and / or KRas G12C activity is desired with an effective amount of a compound of according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 40.

42. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 40.

43. The method of claim 42, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg / kg per day.

44. The method of claim 43, wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg / kg per day.

45. The method of claim 42, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginousexostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial `carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

46. The method of claim 42, wherein the cancer is a KRas G12S-associated cancer.

47. The method of claim 42, wherein the cancer is a KRas G12C-associated cancer.

48. The method of any one of claims 46 or 47, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

49. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12S mutation or a KRas G12C mutation (e.g., a KRas G12S-associated cancer or a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound according to any one of claims 1- 39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 40.

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